Pyrazole derivatives P38 MAP kinase inhibitors

ABSTRACT

The present invention relates to certain pyrazole derivatives of Formula (I):  
                 
 
     that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/305,737, filed May 5, 1999 and claims thebenefit under 35 U.S.C. 119(e) of U.S. Provisional Application SerialNo. 60/084,250, filed May 5, 1998, U.S. Provisional Application SerialNo. 60/122,140, filed Mar. 2, 1999, and U.S. Provisional ApplicationSerial No. 60/130,369, filed Apr. 21, 1999, hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to certain pyrazole derivatives thatinhibit p38 MAP kinase, pharmaceutical compositions containing them,methods for their use, and methods for preparing these compounds.

BACKGROUND INFORMATION AND RELATED DISCLOSURES

[0003] TNF and IL-1 have been shown to be central players in thepathological processes underlying many chronic inflammatory andautoimmune diseases. IL-1 is implicated in mediating or exacerbatingdiseases such as rheumatoid arthritis ((see., Arend, W. P. Arthritis &Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption,toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin'sdisease (see., Benharroch, D.; et. al. Euro. Cytokine Network 7(1):51-57) and Alzheimer's disease. Excessive or unregulated TNF productionhas been implicated in mediating or exacerbating diseases such asrheumatoid arthritis ((see., Maini, R. N.; et. al. APMIS. 105(4):257-263, (1997); Feldmann, M., J. of the Royal College of Physicians ofLondon 30(6): 560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septicshock ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997),adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al.Clin. & Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. &Exp. Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever((see., Cooper, A. L., et. al. Am. J. of Physiology 267(6 Pt. 2):1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.;et al. J. of Neuroimmunol. 72(2): 163-168, (1997)) and periodontaldiseases.

[0004] Clinical trials with IL-1 and TNF receptor antagonists have shownthat blocking the ability of these cytokines to signal through theirreceptors leads to significant improvement, in humans, in inflammatorydiseases. Therefore, modulation of these inflammatory cytokines isconsidered one of the most effective strategies to block chronicinflammation and have positive therapeutic outcomes. It has also beenshown that p38 MAP kinase plays an important role in the translationalcontrol of TNF and IL-1 and is also involved in the biochemicalsignaling of these molecules ((see., Lee, J. C., et al. Nature. 372(6508): 739-46, (1994)). Compounds that bind to p38 MAP are effective ininhibiting bone resorption, inflammation, and other immune andinflammation-based pathologies. The characterization of the p38 MAPkinase and its central role in the biosynthesis of TNF and IL-1 havemade this kinase an attractive target for the treatment of diseasesmediated by these cytokines.

[0005] It would therefore be desirable to provide p38 MAP kinaseinhibitors and thereby provide a means of combating diseases mediated bypro-inflammatory cytokines such as TNF and IL-1. This invention fulfillsthis and related needs.

SUMMARY OF THE INVENTION

[0006] In a first aspect, this invention provides compounds selectedfrom the group of compounds represented by Formula (1):

[0007] wherein:

[0008] R¹ is hydrogen or acyl;

[0009] R² is hydrogen or alkyl;

[0010] A is an aryl or heteroaryl ring;

[0011] B is an aryl or heteroaryl ring;

[0012] R³ is selected from the group consisting of:

[0013] (a) amino, alkylamino or dialkylamino;

[0014] (b) acylamino;

[0015] (c) optionally substituted heterocyclyl;

[0016] (d) optionally substituted aryl or heteroaryl;

[0017] (e) heteroalkyl;

[0018] (f) heteroalkenyl;

[0019] (g) heteroalkynyl;

[0020] (h) heteroalkoxy;

[0021] (i) heteroalkylamino;

[0022] (j) optionally substituted heterocyclylalkyl;

[0023] (k) optionally substituted heterocyclylalkenyl;

[0024] (l) optionally substituted heterocyclylalkynyl;

[0025] (m) optionally substituted cycloalkoxy, cycloalkylalkyloxy,heterocyclylalkoxy, or heterocyclyloxy;

[0026] (n) optionally substituted heterocyclylalkylamino;

[0027] (o) optionally substituted heterocyclylalkylcarbonyl;

[0028] (p) heteroalkylcarbonyl;

[0029] (q) optionally substituted cycloalkylamino;

[0030] (r) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionallysubstituted heterocyclylalkyl;

[0031] (s) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each other,hydrogen, alkyl or heteroalkyl;

[0032] (t) —Y-(alkylene)-R⁹ where:

[0033] Y is a single bond, —O—, —N— or —S(O)_(n)— (where n is an integerfrom 0 to 2); and R⁹ is cyano, optionally substituted heteroaryl, —COOH,—COR¹⁰, —COOR¹¹, —CONR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or—NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl or optionally substituted heterocycle,R¹¹ is alkyl, and R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are,independently of each other, hydrogen, alkyl or heteroalkyl;

[0034] (u) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and R²² independentlyrepresent hydrogen, alkyl or hydroxy, or R²⁰ and R²¹ together are—(CH₂)_(n)— where n is 2 or 3 and R is hydrogen or alkyl;

[0035] (v) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴ are,independently of each other, hydrogen, alkyl or heteroalkyl;

[0036] (w) —CONR²⁵R²⁶ where R²⁵ and R²⁶ independently representhydrogen, alkyl, heteroalkyl or optionally substitutedheterocyclylalkyl, or R²⁵ and R²⁶ together with the nitrogen to whichthey are attached form an optionally substituted heterocyclyl ring;

[0037] (x) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷ isalkyl, heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclylalkyl, or —NR²⁸R²⁹ where R²⁸ and R²⁹ are,independently of each other, hydrogen, alkyl or heteroalkyl;

[0038] (y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

[0039] (z) arylaminoalkylene or heteroarylaminoalkylene;

[0040] (aa) Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—,—N(alkyl)— or —O—, and R³⁰, R³¹ and R³² are independently of each other,hydrogen, alkyl or heteroalkyl;

[0041] (bb) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (where R′ and R″ areindependently hydrogen or alkyl);

[0042] (cc) heteroarylalkenylene or heteroarylalkynylene;

[0043] (dd) X-(alkylene)CH[(CR′R″)_(m)OR⁴⁰][(CR′R″)_(n)OR⁴⁰] where:

[0044] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(p)— (where pis an integer from 0 to 2);

[0045] R⁴⁰ is acyl; C(O)OR⁴¹ (where R⁴¹ is hydrogen, alkyl, orcycloalkyl);

[0046] C(O)ONR⁴¹R⁴² (where R⁴¹ is as defined above and R⁴² is hydrogenor alkyl); or C(O)NR⁴¹R⁴² (where R⁴¹ and R⁴² are as defined above);

[0047] R′ and R″, independently, are hydrogen or alkyl; and

[0048] m and n, independently, are an integer from 0 to 3 provided thatm and n are not both zero;

[0049] (ee) X-(alkylene)-CH(OH)CH₂NHR⁵⁰ where:

[0050] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2); and

[0051] R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, orcycloalkyl and R⁵² is hydrogen or alkyl); and

[0052] (ff) X-(alkylene)-CH(NR⁵⁰)—CH₂OH where:

[0053] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2); and

[0054] R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, orcycloalkyl and R⁵² is hydrogen or alkyl );

[0055] R⁴ is selected from the group consisting of:

[0056] (a) hydrogen;

[0057] (b) halo;

[0058] (c) alkyl;

[0059] (d) alkoxy; and

[0060] (e) hydroxy;

[0061] R⁵ is selected from the group consisting of:

[0062] (a) hydrogen;

[0063] (b) halo;

[0064] (c) alkyl;

[0065] (d) haloalkyl;

[0066] (e) thioalkyl;

[0067] (f) hydroxy;

[0068] (g) amino;

[0069] (h) alkylamino;

[0070] (i) dialkylamino;

[0071] (j) heteroalkyl;

[0072] (k) optionally substituted heterocycle;

[0073] (l) optionally substituted heterocyclylalkyl;

[0074] (m) optionally substituted heterocyclylalkoxy;

[0075] (n) alkylsulfonyl;

[0076] (o) aminosulfonyl, mono-alkylaminosulfonyl ordialkylaminosulfonyl;

[0077] (p) heteroalkoxy; and

[0078] (q) carboxy;

[0079] R⁶ is selected from a group consisting of:

[0080] (a) hydrogen;

[0081] (b) halo;

[0082] (c) alkyl; and

[0083] (d) alkoxy; and

[0084] prodrugs, individual isomers, mixtures of isomers andpharmaceutically acceptable salts thereof.

[0085] In a second aspect, this invention provides pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof Formula (I) or its pharmaceutically acceptable salt and apharmaceutically acceptable excipient.

[0086] In a third aspect, this invention provides a method of treatmentof a disease in a mammal treatable by administration of a p38 MAP kinaseinhibitor, comprising administration of a therapeutically effectiveamount of a compound of Formula (I) or its pharmaceutically acceptablesalt.

[0087] In a fourth aspect, this invention provides processes forpreparing compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0088] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0089] “Alkyl” means a linear saturated monovalent hydrocarbon radicalof one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl,propyl, 2-propyl, pentyl, and the like.

[0090] “Alkylene” means a linear saturated divalent hydrocarbon radicalof one to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., methylene, ethylene,propylene, 2-methylpropylene, pentylene, and the like.

[0091] “Alkenyl” means a linear monovalent hydrocarbon radical of two tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

[0092] “Alkenylene” means a linear divalent hydrocarbon radical of twoto six carbon atoms or a branched divalent hydrocarbon radical of threeto six carbon atoms, containing at least one double bond, e.g.,ethenylene, propenylene, and the like.

[0093] “Alkynyl” means a linear monovalent hydrocarbon radical of two tosix carbon atoms or a branched divalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

[0094] “Alkynylene” means a linear divalent hydrocarbon radical of twoto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbon atoms, containing at least one triple bond, e.g.,ethynylene, propynylene, and the like.

[0095] “Alkoxy” means a radical —OR where R is alkyl as defined above,e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.

[0096] “Acyl” means a radical —C(O)R where R is hydrogen, alkyl,cycloalkyl, or haloalkyl e.g., acetyl, trifluoroacetyl, and the like.

[0097] “Acylamino” means a radical —NRC(O)R′ where R is hydrogen oralkyl, and R′ is alkyl, heteroalkyl or optionally substitutedheterocyclylalkyl, e.g., acetylamino, 2-amino-2-methylpropionamide, andthe like.

[0098] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoroand chloro.

[0099] “Haloalkyl” means alkyl substituted with one or more same ordifferent halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and thelike.

[0100] “Aryl” means a monovalent monocyclic or bicyclic aromatichydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl,2-naphthyl, and the like. The aryl ring may optionally be fused to a 5-,6- or 7- membered monocyclic saturated ring optionally containing 1 or 2heteroatoms independently selected from oxygen, nitrogen or sulfur, theremaining ring atoms being C where one or two C atoms are optionallyreplaced by a carbonyl group. Representative aryl radicals with fusedrings include, but are not limited to, 2,3-dihydrobenzo[1,4]dioxan,chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran,benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, andthe like.

[0101] “Heteroaryl” means a monovalent monocyclic or bicyclic aromaticradical of 5 to 10 ring atoms containing one, two, or three ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.The term also includes those radicals where a heteroatom within the ringhas been oxidized or quaternized, such as, for example, to form anN-oxide or a quaternary salt. Representative examples include, but arenot limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyriridinyl,pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl,benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl,triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl,N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl,oxazolonyl, and their corresponding N-oxides, (e.g. pyridyl N-oxide,quinolinyl N-oxide), their quaternary salts and the like.

[0102] “Cycloalkyl” means a cyclic nonaromatic hydrocarbon radical of 3to 8 ring atoms, where one or two C atoms are optionally replaced by acarbonyl group. Representative examples include, but are not limited tocyclopropyl, cyclopentyl, cyclohexyl, and the like.

[0103] “Heterocycle” or “heterocyclyl” means a cyclic nonaromaticradical of 3 to 8 ring atoms in which one, two, or three ring atoms areheteroatoms selected from N, O, or S(O)_(n) (where n is an integer from0 to 2), the remaining ring atoms being C where one or two C atoms areoptionally replaced by a carbonyl group. The term also includes thoseradicals where a ring nitrogen atom has been oxidized or quaternized,such as, for example, to form an N-oxide or a quaternary salt.Representative examples include, but are not limited to,tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino,morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl,2,2-dimethyl-1,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl,2-imidazolidonyl, S,S-dioxothiomorpholino, and the like.

[0104] “Heterocycloamino” means a saturated monovalent cyclic group of 4to 8 ring atoms, wherein at least one ring atom is N and optionallycontains one additional ring atom selected from N or O, the remainingring atoms being C. The term includes groups such as pyrrolidino,piperidino, morpholino, piperazino and the like.

[0105] “Optionally substituted aryl, heteroaryl, cycloalkyl, orheterocyclyl” means an aryl, heteroaryl, cycloalkyl, or heterocyclylring as defined above, which is optionally substituted independentlywith one or two substituents selected from alkyl, phenyl, benzyl,haloalkyl, heteroalkyl, halo, cyano, cycloalkyl, acyl, —OR (where R ishydrogen or alkyl), —NRR′ (where R and R′ are independently selectedfrom hydrogen, alkyl or acyl), —NHCOR (where R is alkyl), —NRS(O)_(n)R′(where R is hydrogen or alkyl, n is an integer from 0 to 2 and R′ ishydrogen, alkyl or heteroalkyl), —NRS(O)_(n)NR′R″ (where R is hydrogenor alkyl, n is an integer from 0 to 2 and R′ and R″ are independentlyhydrogen, alkyl or heteroalkyl), —S(O)_(n)R (where n is an integer from0 to 2 and R is hydrogen, alkyl or heteroalkyl), —S(O)_(n)NRR′ (where nis an integer from 0 to 2 and R and R′ are independently hydrogen, alkylor heteroalkyl), —COOR, -(alkylene)COOR (where R is hydrogen or alkyl),—CONR′R″ or -(alkylene)CONR′R″ (where R′ and R″ are independentlyhydrogen or alkyl).

[0106] “Heteroalkyl” means an alkyl radical as defined above, carryingone, two or three substituents selected from —NR^(a)R^(b), —OR^(c)wherein R^(a), R^(b) and R^(c) are independently of each other hydrogen,alkyl, cycloalkyl, or acyl, or R^(a) and R^(b) together formheterocycloamino group. Representative examples include, but are notlimited to, hydroxymethyl, acetoxymethyl, 3-hydroxypropyl,1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl,2-acetylaminoethyl, 3-(pyrrolidin-1-yl)ethyl and the like.

[0107] “Heteroalkenyl” means an alkenyl radical as defined above,carrying one or two substituents selected from —NR^(a)R^(b), —OR^(c) or—S(O)_(n)R^(d) wherein R^(a), R^(b) and R^(c) are independently of eachother hydrogen or alkyl, and R^(d) is alkyl or —NRR′ (where R and R′ areindependently of each other hydrogen or alkyl. Representative examplesinclude, but are not limited to, 3-hydroxy-1-propenyl,3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, andthe like.

[0108] “Heteroalkynyl” means an alkynyl radical as defined above,carrying one or two substituents selected —NR^(a)R^(b), OR^(c),—S(O)_(n)R^(d) or —S(O)_(n)NRR′ (where R and R′ are independently ofeach other hydrogen or alkyl) wherein R^(a), R^(b) and R^(c) areindependently of each other hydrogen or alkyl, and R^(d) is alkyl and nis an integer from zero to two. Representative examples include, but arenot limited to, 3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl and thelike.

[0109] “Heteroalkoxy” means a radical —OR where R is heteroalkyl groupas defined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 2,3-dihydroxy-1-methylpropoxy, 2-aminoethoxy, andthe like.

[0110] “Heteroalkylamino” means a radical —NR^(a)R^(b) where R^(a) ishydrogen or alkyl, and R^(b) is a heteroalkyl group as defined above,e.g., 2-hydroxyethylamino, 3-dimethylaminopropylamino, and the like.

[0111] “Optionally substituted heterocyclylalkyl” means a radical—R^(a)R^(b) where R^(a) is an alkylene group, and R^(b) is an optionallysubstituted heterocyclyl group as defined above e.g.,2-(morpholin-4-yl)ethyl, 3-(piperidin-1-yl)-2-methylpropyl, and thelike.

[0112] “Optionally substituted heterocyclylalkenyl” means a radical—R^(a)R^(b) where R^(a) is an alkenylene group and R^(b) is anoptionally substituted heterocyclyl group as defined above e.g.,3-(morpholin-4-yl)prop-1-enyl, 3-(piperidin-1-yl)prop-1-enyl,3-(4-methylpiperazin-1-yl)prop-1-enyl, and the like.

[0113] “Optionally substituted heterocyclylalkynyl” means a radical—R^(a)R^(b) where R^(a) is an alkynyl group and R^(b) is an optionallysubstituted heterocyclyl group as defined above e.g.,3-(morpholin-4-yl)prop-1-ynyl, 3-(piperidin-1-yl)lprop-1-ynyl, and thelike.

[0114] “Optionally substituted “cycloalkoxy” means a radical —OR where Ris an optionally substituted cycloalkyl as defined above, e.g.cyclopentyloxy, cyclohexyloxy, and the like.

[0115] “Optionally substituted heterocyclyloxy” means a radical —ORwhere R is an optionally substituted heterocyclyl group as definedabove, piperidin-2-yloxy, pyrrolidin-3-yloxy, piperazin-2-yloxy, and thelike.

[0116] “Optionally substituted heterocyclylalkoxy” means a radical —ORwhere R is an optionally substituted heterocyclylalkyl group as definedabove, e.g., 2-(morpholin-4-yl)-ethoxy, 3-(piperazin-1-yl)propoxy,2-(2-oxopyrrolidin-1-yl)ethoxy, and the like.

[0117] “Optionally substituted cycloalkylamino” means a radical—NR^(a)R^(b) where R^(a) is hydrogen or alkyl and R^(b) is an optionallysubstituted cycloalkyl group as defined above, e.g., cyclopropylamino,cyclohexylamino, 3,4-dihydroxycyclopentylamino, and the like.

[0118] “Optionally substituted heterocyclylalkylamino” means a radical—NR^(a)R^(b) where R^(a) is hydrogen or alkyl and R^(b) is an optionallysubstituted heterocyclylalkyl group as defined above, e.g.,2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-1-yl)propylamino, and thelike.

[0119] “Optionally substituted heteroaralkyloxy means a radical —O—R^(a)where R^(a) is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy,2-[3(2H)-pyridazon-1-yl]ethoxy and the like.

[0120] “Optional” or “optionally” means that the subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group optionally mono- ordi-substituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where the arylgroup is mono- or disubstituted with an alkyl group and situations wherethe heterocyclo group is not substituted with the alkyl group.

[0121] “Amino protecting group” refers to those organic groups intendedto protect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trifluoroacetyl, and the like.

[0122] The compounds of this invention may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)- stereoisomers or as mixtures thereof. Unlessindicated otherwise, the description or naming of a particular compoundin the specification and claims is intended to include both individualenantiomers and mixtures, racemic or otherwise, thereof. The methods forthe determination of stereochemistry and the separation of stereoisomersare well-known in the art (see discussion in Chapter 4 of “AdvancedOrganic Chemistry”, 4th edition J. March, John Wiley and Sons, New York,1992).

[0123] A “pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

[0124] A “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

[0125] (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

[0126] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

[0127] “Pro-drugs” means any compound which releases an active parentdrug according to Formula (I) in vivo when such prodrug is administeredto a mammalian subject. Prodrugs of a compound of Formula (I) areprepared by modifying functional groups present in the compound ofFormula (I) in such a way that the modifications may be cleaved in vivoto release the parent compound. Prodrugs include compounds of Formula(I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy functional groups in compounds of Formula (I), and the like.

[0128] “Treating” or “treatment” of a disease includes:

[0129] (1) preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease,

[0130] (2) inhibiting the disease, i.e., arresting or reducing thedevelopment of the disease or its clinical symptoms, or

[0131] (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

[0132] A “therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Nomenclature

[0133] The naming and numbering of the compounds of this invention isillustrated below.

[0134] The nomenclature used in this application is generally based onthe IUPAC recommendations, e.g., a compound of formula (I):

[0135] where R¹, R², R⁴, R⁶ are hydrogen,

[0136] is 4-(3-hydroxypropyl)phenyl and

[0137] is 4-fluorophenyl is named5-amino-1-(4-fluorophenyl)-4-[4-(3-hydroxypropyl)-benzoyl]pyrazole.

[0138] where R¹, R², R⁴, R⁶ are hydrogen,

[0139] is 3-[3-(morpholin-4-yl)prop-1-ynyl]-phenyl and

[0140] is 4-fluorophenyl is named5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazole.

[0141] Representive compounds of this invention are as follows:

[0142] Compounds of Formula (I) where R¹, R² and R⁴ are hydrogen, B isphenyl and the other groups are as defined below are:

CPD #

R⁵ R⁶ M. Pt. ° C. Mass Spec. (M⁺) 1 4-(3-hydroxypropyl)phenyl H H148-152.5 2 4-[3-(morpholin-4-yl)prop-1-enyl]phenyl 4-F H 166.7-168.2 33-[3-(morpholin-4-yl)prop-1-ynyl]phenyl 4-F H 145.2-145.8 43-[3-(morpholin-4-yl)prop-1-ynyl]phenyl 4-F H 161.6-162.8 54-[3-(morpohlin-4-yl)propyl]phenyl 4-F.HCl H 408 63-[3-(morpholin-4-yl)propyl]phenyl 4-F.HCl H 211.9-212.6 73-(3-hydroxyprop-1-ynyl)phenyl 4-F H 219.2-219.6 83-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]phenyl 4-F.2HCl H 270.8-271.1 93-[3-(piperidin-1-yl)prop-1-ynyl]phenyl 4-F.HCl H 205.3-207.4 103-(2-aminosulfonylethenyl)phenyl 4-F H 370 11 3-cyanomethyloxyphenyl 4-FH 12 3-[3-dimethylaminoprop-1-ynyl)]phenyl 4-F.HCl H 229.9-230 133-[2-(morpholin-4-yl)ethoxy]phenyl 4-F H 143-[2-(morpholin-4-yl)ethoxy]phenyl 4-F.HCl H 191.6-192.5 153-[2-(morpholin-4-yl)ethoxy]phenyl 2-F 4-F 428 163-(3-methylaminoprop-1-ynyl)phenyl 4-F H 210.6-210.8 173-(4-methylpiperazin-1-yl)phenyl 2-F.HCl H 142.5-151 183-(morpholin-4-ylmethylcarbonyl)phenyl 4-F.HCl H 408 193-(formamidoxine)phenyl 4-F H 227-231.8 20 3-(pyridin-3-yl)phenyl 4-F H222.4-223.0 21 3-[3-(piperidin-1-yl)propoxy]phenyl 4-F H 422 223-[2-(piperidin-1-yl)ethoxy]phenyl 4-F H 408 233-[3-(morpholin-4-yl)propoxy]phenyl 4-F H 424 243-[3-(4-methylpiperazin-1-yl)propoxy]phenyl 4-F H 437 253-[3-(2-hydroxymethylpyridin-1-yl)propoxy]- 4-F H 438 phenyl 263-[3-(2-aminocarbonylpyrrolidin-1-yl)propoxy]- 4-F H phenyl 273-(3-cyanopropoxy)phenyl 4-F H 364 28 3-(3-diethylaminopropoxy)phenyl4-F H 410 29 2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl 4-F H 437 303-[3-(4-methylpiperazin-1-yl)propyl]phenyl 4-F.2HCl H 254.5-254.9 313-[3-(4-methylpiperazin-1-yl)ethyl]phenyl 4-F.2HCl H 272.9-273.9 323-[3-(piperidin-1-yl)propyl]phenyl 4-F.HCl H 227.1-277.7 333-(4-benzylpiperidin-1-yl)phenyl 4-F H 156.2-160.9 343-(methylaminocarbonylmethyloxy)phenyl 4-F H 195.6-196.3 353-(morpholin-4-ylcarbonylmethyloxy)phenyl 4-F H 124.3-126.6 363-(piperidin-1-ylcarbonylmethyloxy)phenyl 4-F H 422 373-(diethylaminocarbonylmethyloxy)phenyl 4-F H 410 383-(4-methylpiperazin-1-ylcarbonylmethyloxy)phenyl 4-F H 437 393-(2-dimethylaminoethoxy)phenyl 4-F H 368 403-(methylcarbonylmethyloxy)phenyl 4-F H 353 413-[4-(2-hydroxyethyl)piperazin-1- 4-F H 467 ylcarbonylmethyloxy-phenyl42 3-[3-(RS)-hydroxypyrrolidin-1- 4-F H 438 ylcarbonylmethyloxy]-phenyl43 3-aminophenyl 4-F H 165.2-165.8 44 3-(3-imidazol-1-ylpropoxy)phenyl4-F H 405 45 3-[3-(4-(RS)-hydroxypiperidin-1-yl)propoxy]phenyl 4-F H 43846 3-(piperazin-1-yl)phenyl 4-F.2HCl H 163.2-163.6 473-(2-aminoethyl)phenyl 4-F.HCl H 240.6-240.8 483-[3-(morpholin-4-yl)propylamino]phenyl 4-F H 423 493-[2-(morpholin-4-yl)ethylamino]phenyl 4-F H 409 503-(2-aminosulfonylethyl)phenyl 4-F H 170-170.4 513-(piperidin-3-yl)phenyl 4-F H 222.4-223 523-(3-dimethylaminopropylamino)phenyl 4-F H 381 533-[2-(3-(RS)-hydroxypyrrolidin-1- 4-F H 423 yl)ethylamino]phenyl 543-(2-hydroxyethoxy)phenyl 4-F H 341 553-[3-(morpholin-4-yl)prop-1-ynyl]phenyl 2-F 4-F 190.4-191.2 563-[3-(morpholin-4-yl)propyl]phenyl 2-F 4-F 226.4-227.5 573-(2-aminopyridin-5-yl)phenyl 2-F.HCl 4-F 281.2-281.6 583-(pyrimidin-3-yl)phenyl 4-F H 237-241 593-(1-methylpyridin-3-yl)phenyl.iodide 4-F H 191.1-192.4 603-(N-oxidopyridin-3-yl)phenyl 2-F 4-F 251.1-251.7 613-(pyridin-4-yl)phenyl 2-F.HCl 4-F 218-226 376 623-(2-aminopyrimidin-5-yl)phenyl 2-F.HCl 4-F 272-275 633-(2-amino-6-methylpyridin-5-yl)phenyl 2-F.HCl 4-F 215-217 643-(6-methylpyridin-2-yl)phenyl 2-F.HCl 4-F 268-279 653-(pyridin-3-yl)phenyl 4-NMeHCl H 281.3-282.8 66 3-(pyridin-3-yl)phenylH.HCl 3-MeO 256.1-256.5 67 3-(pyridin-3-yl)phenyl 3-HO.HCl H 269-273 683-(pyridin-3-yl)phenyl 4-sulfamoyl H.HCl >300 419 693-(pyridin-3-yl)phenyl 2-Me.HCl 4-Me 250.7-251.8 703-(N-oxidopyridin-3-yl)phenyl 2-Me H 190.5-191.2 713-(N-oxidopyridin-3-yl)phenyl 4-Me H 212-213.5 723-(2,6-dimethylpyridin-3-yl)phenyl 2-F.HCl 4-F >300 440.879 733-(pyridin-3-yl)phenyl 2-Me.HCl 4-Cl 425.317 74 3-(pyridin-3-yl)phenyl3-Me.HCl 4-Me 404.899 75 3-(pyridin-3-yl)phenyl 4- H.HCl 454.936methylsulfonyl 76 3-(pyridin-3-yl)phenyl 2-Et.HCl H 404.899 773-(imidazol-2-yl)phenyl 2-F.HCl 4-F 78 3-(3-ethoxycarbonylphenyl)phenyl4-F H 267.4-268.7 79 3-(pyridin-3-yl)phenyl 3-OH.HCl H 803-(3-carboxyphenyl)phenyl 4-F H 117-128 429 813-{2-(piperidin-1-ylethoxy)}phenyl 4-F.HCl H 210.2-211.2 823-(pyridin-2-ylmethoxy)phenyl 4-F H 176.1-177.3 833-isopropylaminocarbonyloxyphenyl 4-F H 225.2-230.1 843-ethylaminocarbonyloxyphenyl 4-F H 201.2-202.8 853-(1,2-dihydroxyethyl)phenyl 4-F H 52-56 341.34 863-(1-piperidinylmethyl)phenyl 2-F 4-F 116.6-118.6 396.439 873-(3-hydroxy-3-methyl-but-1-ynyl)phenyl 4-F H 152.6-153.1 883-(3-pyridylethylnyl)phenyl 2-F 4-F 183.5-184.0 893-{3-(S,S-dioxo-thiomorpholin-4-yl)-1- 2-F 4-F 190.1-191.2propynyl}phenyl 90 3-(3-hydroxy-3-methylbutyl)phenyl 4-F H 101.3-102.891 3-(3-pyridylethyl)phenyl 2-F 4-F 153.4-153.7 923-{3-(S,S-dioxo-thiomorpholin-4-yl)propyl}phenyl 2-F 4-F 123.8-125.9 933-{2-(1-hydroxycyclopentyl)ethyl}phenyl 2-F H 128.4-129.7 943-{2-(1-hydroxycyclopentyl)ethynyl}phenyl 2-F 4-F 176.8-177.1 953-{2-(1-hydroxycyclopentyl)ethyl}phenyl 2-F 4-F 120.3-121 963-(3-hydroxybutyl)phenyl 2-F 4-F 111.1-112.6 973-{2-(morpholin-4-yl)ethoxy}phenyl 2-F H 130.8-135.1 983-{2-(morpholin-4-yl)ethoxy}phenyl 2-Cl 6-Cl 144.2-145.1 993-(pyridin-3-yl)phenyl 2-F.HCl 4-F 256.5-257.7 1003-(2-methylsulfonylethyl)phenyl 4-F H 151.5-155.6 1013-(2-methylsulfonylethyl)phenyl 2-F 4-F 157.2-157.7 1023-(2-ethylsulfonylethenyl)phenyl 2-F 4-F 101.6-105.6 1033-(1,2-dihydroxyethyl)phenyl 2-F 4-F 59-64 1043-(2,2-dimethyl-1,3-dioxolan-5-yl)phenyl 4-F H 94.5-100 1053-hydroxymethylphenyl 2-F 4-F 155.4-156.5 1063-[2(R),3-dihydroxypropoxy]phenyl 4-F H 150.2-153.0 1073-[2(S),3-dihydroxypropoxy]phenyl 4-F H 149.9-153.0 1083-(2-hydroxyethylsulfonyl)phenyl 2-F 4-F 92.1-93.8 1093-(1,2-dihydroxyethyl)phenyl 2-Me H 83.0-85.5 1103-[2-(N-oxidomorpholin-4-yl)ethoxy]phenyl 4-F H 185-186dec 1113-[2-(morpholin-4-yl)ethoxy]phenyl 2-F 6-F 178.9-181.2 1123-(2,3-dihydroxypropyl)phenyl 2-F 4-F 140-142 1133-(2-hydroxyethoxy)phenyl 4-F H 165.3-166.7 114 2-thienyl 4-F H 287 1152-furyl 4-F H 271 116 2-methyl-3-furyl 2-F 4-F 117 6-quinolinyl 2-F 4-F220-259.2 118 2-hydroxyethylphenyl 4-F H 154.5-155.0 1193-carboxymethyloxyphenyl 4-F H 215.9-216.2 120 3-(pyridin-3-yl)phenyl2-Me H 223.7-225.1 146 3-(3-sulfamoylphenyl)phenyl 4-F H 214.6-217.5 1473-(3-methylsulfonylphenyl)phenyl 4-F H 148 3-methylsulfonylmethylphenyl4-F H 373 149 3-sulfamoylmethylphenyl 4-F H 150 3-carboxymethylphenyl4-F H 151 3-(2-hydroxyethylsulfonyl)phenyl 4-F H 1523-(2-hydroxy-3-methoxypropoxy)phenyl 4-F H 113.1-114.2 1533-oxiranylmethoxyphenyl 4-F H 154 3-[2(R),3-dihydroxypropoxy]phenyl 2-F4-F 115.6-116.9 155 3-[2(R),3-dihydroxypropoxy]phenyl 2-Me H 368 (M + H)156 3-[2(R),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4- H 433methylsulfonyl 157 3-[2(R),3(R)-dihydroxy-3-methylpropoxy]phenyl 4-F H158 3-[2(R),3(S)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1593-[2(S),3(S)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1603-[2(S),3(R)-dihydroxy-3-methylpropoxy]phenyl 4-F H 1613-[2(R),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4-F H 1623-[2(S),3-dihydroxy-3,3-dimethylpropoxy]phenyl 4-F H 1633-[3,4-dihydroxycyclopentyloxy]phenyl 4-F H 64-69 1643-[2,3-dihydroxy-1-methylpropoxy]phenyl 4-F H 1653-[2(S),3-(diacetoxy)propoxy]phenyl 4-F H 91.4-92.7 1663-[2(S),4-(diisobutanoyloxy)propoxy]phenyl 4-F H 60.5-62 1673-[2(S),3-(dipivaloyloxy)propoxy]phenyl 4-F H 132.7-133.8 1683-[2(S),3-(dimethoxycarbonyloxy)propoxy]phenyl 4-F H 62-65 1693-[2,2-(dihydroxymethyl)ethoxy]phenyl 4-F H 80.4-88.9 1703-[(2.2-dimethyl-1,3-dioxolan-4(S)-yl)methoxy] 4.F H 78.3-80.0 phenyl171 3-[(1,3-dioxolan-2-on4(R)-yl)methoxy]phenyl 4-F H 144.3-144.9 1723-[(2-thioxo-1,3-dioxolan-4-yl)methoxy]phenyl 4-F H 125.4-126 1733-[(2,2-diethyl-1,3-dioxolan-4(S)-yl)methoxy]phenyl 4-F H 74.1-75.7 1743-[(2-methyl-2-ethyl-1,3-dioxolan-4(S)- 4-F H 81.1-83.0yl)methoxy]phenyl

PREFERRED EMBODIMENTS

[0143] While the broadest definition of this invention is set forth inthe Summary of the Invention, certain compounds of Formula (I) arepreferred.

[0144] For example, a preferred group of compounds is that wherein R³ isselected from:

[0145] (a) optionally substituted heterocyclyl;

[0146] (b) aryl or heteroaryl both optionally substituted with asubstituent selected from halo, alkyl, amino, alkoxy, carboxy, loweralkoxy carbonyl, SO₂R′ (where R′ is alkyl) or SO₂NHR′R″ (where R′ and R″are independently hydrogen or alkyl);

[0147] (c) heteroalkyl;

[0148] (d) heteroalkenyl;

[0149] (e) heteroalkylamino;

[0150] (f) heteroalkoxy;

[0151] (g) optionally substituted heterocyclylalkyl; heterocyclyloxy;cycloalkoxy or cycloalkylalkyloxy;

[0152] (h) optionally substituted heterocyclylalkenyl;

[0153] (i) optionally substituted heterocyclylalkynyl;

[0154] (j) optionally substituted heterocyclylalkoxy;

[0155] (k) optionally substituted heterocyclylalkylamino orcycloalkylamino;

[0156] (l) optionally substituted heterocyclylalkylcarbonyl;

[0157] (k) —Y-(alkylene)-R⁹ where Y is a single bond, —O— or —N— and R⁹is optionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴, —SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷, R¹⁵ andR¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl;

[0158] (l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

[0159] (m) arylaminoalkylene or heteroarylaminoalkylene; or

[0160] (n) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)- or —O—, andR³⁰ and R³¹ are independently of each other, hydrogen, alkyl orheteroalkyl.

[0161] Within the above preferred group, more preferred groups ofcompounds are those wherein, A and B are aryl, preferably phenyl.

[0162] Within the above preferred and more preferred groups, an evenmore preferred group of compounds is that wherein:

[0163] R¹ is hydrogen;

[0164] R² is hydrogen or alkyl, preferably hydrogen or methyl, morepreferably hydrogen;

[0165] R⁴ is hydrogen, halo or alkyl, preferably hydrogen, chloro,fluoro or methyl, more preferably hydrogen;

[0166] R⁵ is halo or alkyl; and

[0167] R⁶ is hydrogen, halo, alkyl, or alkoxy.

[0168] Within the above preferred and more preferred groups, aparticularly preferred group of compounds is that wherein R³ is at the3-position and is optionally substituted heteroaryl, preferablypyridinyl, N-oxidopyridinyl or pyridonyl.

[0169] Another particularly preferred group of compounds is that whereinR³ is at the 3-position and is optionally substituted phenyl, preferablysulfamoylphenyl, alkylsulfamoylphenyl, carboxyphenyl, carboxamidophenyl,alkoxycarbonylphenyl, alkylaminocarbonylphenyl ordialkylaminocarbonylphenyl.

[0170] A third particularly preferred group of compounds is thatwherein:

[0171] R³ is at the 3-position and is selected from:

[0172] (a) heteroalkyl;

[0173] (b) heteroalkoxy;

[0174] (c) heteroalkylamino;

[0175] (d) optionally substituted heterocyclylalkyl;

[0176] (e) optionally substituted heterocyclylalkoxy, cycloalkoxy; orcycloalkylalkyloxy;

[0177] (f) optionally substituted heterocyclylalkylamino;

[0178] (g) —Y-(alkylene)-R⁹ where Y is a single bond, —O— or —N— and R⁹is optionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴, —SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷, R¹⁵ andR¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl; or

[0179] (h) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)- or —O—, andR³⁰ and R³¹ are independently of each other, hydrogen, alkyl orheteroalkyl.

[0180] Within the above preferred group, a preferred group of compoundsis that wherein R³ is at the 3-position and is heteroalkyl.

[0181] Preferred groups for R³ 2-dimethylaminoethyl,3-dimethylaminopropyl, 4-dimethylaminobutyl, hydroxymethyl,1,2-dihydroxyethyl, 3-hydroxy-3-methylbutyl or 3-hydroxybutyl.

[0182] Another preferred group of compounds is that wherein R³ isselected from the group including: amino, 3-dimethylaminopropoxy,2-dimethylaminoethoxy, 2-hydroxyethoxy, 2-dimethylaminoethylamino,3-dimethylaminopropylamino, 3-dimethylaminoprop-1-enyl,3-dimethylaminoprop-1-ynyl, and 2-dimethylaminoethylcarbonyl.

[0183] Another group of preferred groups for R³ is selected from3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy,3-(morpholin-4-yl)propyl, 2-(morpholin-4-yl)ethyl,4-(morpholin-4-yl)butyl, 3-(morpholin-4-yl)propylamino,2-(morpholin-4-yl)-ethylamino, 3-(morpholin-4-yl)-prop-1-enyl,3-(morpholin-4-yl)prop-1-ynyl, 4-methylpiperazin-1-yl, piperazin-1-yl,pyridin-3-yl, morpholin-4-ylmethylcarbonyl, 3-dimethylaminoprop-1-enyl,3-dimethylaminoprop-1-ynyl, 2-aminosulfonylethyl,2-aminosulfonylethenyl, acetylamino and trifluoroacetylamino, preferably2-(morpholin-4-yl)ethoxy and 3-(morpholin-4-yl)-propyl.

[0184] A fourth group of particularly preferred compounds is that whereR⁵ is halo or alkyl and R⁶ is hydrogen, halo or alkyl, preferably R⁵ is4-F or 2-Me and R⁶ is hydrogen, or R⁵ is 2-F and R⁶ is 4-F.

[0185] Another group of preferred compounds is that where A and B arearyl, preferably phenyl, and R³ is at the three position and is selectedfrom: heteroalkoxy, optionally substituted heterocyclylalkoxy,optionally substituted cycloalkoxy, and optionally substitutedheterocyclylalkylamino.

[0186] Preferred groups for R³ include 2,2-(dihydroxymethyl)ethoxy,2,3-dihydroxypropoxy, (2,2-dimethyl-1,3-dioxolan-4(S)-yl)methoxy,(2,2-diethyl-1,3-dioxolan-4(S)-yl)methylamino,(1,3-dioxolan-2-on-4(R)-yl)methoxy, (2-thioxo-1,3-dioxolan-4-yl)methoxy,(2,2-diethyl-1,3-dioxolan-4(S)-yl)methoxy,2-methyl-2-ethyl-1,3-dioxolan4(S)-yl)methoxy, and3,4-(dihydroxy)cyclopentyloxy.

[0187] Within the above preferred group, another preferred group ofcompounds is that wherein:

[0188] R¹ is hydrogen,

[0189] R² is hydrogen or alkyl, preferably hydrogen or methyl;

[0190] R⁴ is hydrogen or alkyl;

[0191] R⁵ is halo; and

[0192] R⁶ is hydrogen or alkyl.

[0193] Another preferred group of compounds is that wherein R³ is at the3-position and is selected from:

[0194] (a) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷ isalkyl, heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclylalkyl, or —NR²⁸R²⁹ where R²⁸ and R²⁹ are,independently of each other, hydrogen, alkyl or heteroalkyl;

[0195] (b) X-(alkylene)CH[(CR′R″)_(m)OR⁴⁰][(CR′R″)_(n)OR⁴⁰] where:

[0196] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(p)— (where pis an integer from 0 to 2);

[0197] R⁴⁰ is acyl; C(O)OR⁴¹ (where R⁴¹ is hydrogen, alkyl, orcycloalkyl);

[0198] C(O)ONR⁴¹R⁴² (where R⁴¹ is as defined above and R⁴² is hydrogenor alkyl); or C(O)NR⁴¹R⁴² (where R⁴¹ and R⁴² are as defined above);

[0199] R′ and R″, independently, are hydrogen or alkyl; and

[0200] m and n, independently, are an integer from 0 to 3 provided thatm and n are not both zero;

[0201] (c) X-(alkylene)-CH(OH)CH₂NHR⁵⁰ where:

[0202] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2);

[0203] R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, orcycloalkyl and R⁵² is hydrogen or alkyl); and

[0204] (d) X-(alkylene)-CH(NR⁵⁰)—CH₂OH where:

[0205] X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2);

[0206] R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, orcycloalkyl and R⁵² is hydrogen or alkyl).

[0207] Preferred groups for R³ within this group include2(S),3-(diacetoxy)propoxy, 2(S),3-(diisobutanoyloxy)propoxy,2(S),3-(dipivaloyloxy)propoxy, and 2(S),3-(dimetaoxycarbonyloxy).

[0208] Exemplary particularly preferred compounds are:

[0209]5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole.

[0210]5-amino-1-(2,4-difluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.

[0211] 5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole.

[0212]5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.

[0213]5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

[0214] 5-amino-4-(3-acetylaminobenzoyl)-1-phenylpyrazole.

[0215] 5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

[0216]5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino)benzoyl]pyrazole.

[0217]5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

[0218] 5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.

[0219] 5-amino-1-(2-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.

[0220]5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole.

[0221]5-amino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-1-(4-fluorophenyl)pyrazole.

[0222]5-amino-4-[3-(1,2-dihydroxyethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.

[0223] 5-amino-1-(4-fluorophenyl)-4-[3-sulfamoylbenzoyl]pyrazole.

[0224]5-amino-1-(4-fluorophenyl)-4-{3-[(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methoxy]benzoyl}pyrazole.

[0225]5-amino-1-(4-fluorophenyl)-4-{3-[2(S),3-(diacetoxy)propoxy]benzoyl}pyrazole.

[0226]5-amino-1-(4-fluorophenyl)-4-{3-[2(S),3-(dimethoxycarbonyloxy)propoxy]benzoyl}pyrazole.

[0227]5-amino-1-(4-fluorophenyl)-4-{3-[(1,3-dioxolan-2-on-4(R)-yl)methoxy]benzoyl}pyrazole.

[0228]5-amino-1-(4-fluorophenyl)-4-{3-[(2-thioxo-1,3-dioxolan-4-yl)methoxy]benzoyl}pyrazole.

General Synthetic Scheme

[0229] Compounds of this invention can be made by the methods depictedin the reaction schemes shown below.

[0230] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 140 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

[0231] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula (I)

[0232] Schemes A, B and C describe methods to generate the compounds ofFormula (I).

[0233] In general, compounds of Formula (I) can be prepared by followingeither method (a) or (b) as described below.

[0234] Method (a)

[0235] Reaction of a 2-ketoacetonitrile of formula 1 [where Z is halo(e.g., bromo or iodo), alkoxy, nitro or acetylamino] withN,N-diphenylformamidine gives a 2-keto-3-phenylaminoacrylonitrile offormula 2. The reaction occurs upon heating in a high boiling aromatichydrocarbon such as toluene, xylene, and the like.

[0236] In general, compounds of formula 1 are either commerciallyavailable or they can be prepared by methods well known in the art. Forexample, 2-aroylacetonitriles of formula 1 such as4-methoxybenzoylacetonitrile, 3-nitrobenzoylacetonitrile arecommercially available. Others can be prepared by treating acetonitrilewith a base such as n-butyllithium followed by reaction of the formedacetonitrile anion with an aroyl/heteroaroyl halide or anaryl/heteroaryl ester as described in Sjogren, E. B., et al., J. Med.Chem, 34, 3295, (1991).

[0237] Reaction of the 2-keto-3-phenylaminoacrylonitrile of formula 2with a hydrazine of formula 3 provides a 5-amino-4-ketopyrazole offormula 4. This reaction is generally carried out in a polar solventsuch as ethanol, isopropanol, and the like. Aryl/heteroaryl hydrazinesof formula 2 such as 2- or 3-chlorophenylhydrazine, 2-,3-, or4-fluorophenylhydrazine, phenylhydrazine, 2-hydrazinopyridine,2-hydrazinobenzothiazole, 2-hydrazinoquinoline etc., are commerciallyavailable.

[0238] Compound 4 is then converted to a compound of Formula (I) whereR¹ is hydrogen and R³ is as defined in the Summary of the Invention bymethods well known in the art. Some such procedures are described below.

[0239] (i) A compound of Formula (I) where R³ is heterocyclylalkoxy canbe prepared by the following methods:

[0240] (a) A compound of Formula (I) where R³ is heterocyclylalkoxy canbe prepared from a compound of formula 4 where Z is alkoxy as shownbelow:

[0241] A compound of Formula (I) where R³ is heterocyclylalkoxy can beprepared from a compound of formula 4 where Z is alkoxy by firstde-alkylating the alkoxy group to give the corresponding compound offormula 5 where Z is hydroxy followed by reaction with aheterocyclylalkyl halide [e.g., 4-(2-chloroethyl)morpholine,1-(2-chloroethyl)pyrrolidine, and the like]. The de-alkylation reactionis carried out either with boron tribromide in a halogenated organicsolvent such as dichloromethane or by heating 4 in neat pyridiniumhydrochloride. The alkylation is carried out in the presence of a base(such as potassium carbonate, cesium carbonate, and the like) in a polarorganic solvent such as acetonitrile, dimethylformamide, acetone, andthe like.

[0242] (b) Alternatively, a heterocyclylalkyl group can be attached byreacting 5 with an alkyl dihalide followed by the reaction of theresulting haloalkoxy intermediate with a heterocyclyl group (e.g.,piperazine, morpholine, pyrrolidine, and the like) under the reactionconditions described above. Alkyl dihalides such as1-bromo-2-chloroethane, 1-chloro-3-iodopropane, and the like, arecommercially available.

[0243] (c) Other compounds of Formula (I) where R³ is heterocyclylalkoxy(such as in Example 25 where the heterocycle is an optionallysubstituted cyclic ketal) can be prepared by converting a compound offormula 5 to a bishydroxy alkoxy derivative (such as the diol of Example24), followed by treatment with a ketone or an aldehyde under acidicconditions.

[0244] (d) Other compounds of Formula (I) where R³ is aheterocyclylalkoxy (such as in Example 28 where the heterocycle is acyclic carbonate) can be prepared by converting a compound of formula 5to a bishydroxy alkoxy derivative (such as the diol of Example 24),followed by treatment with a carbonylating reagent such as phosgene,diphosgene, or triphosgene.

[0245] (ii) A compound of Formula (I) where R³ is —O-(alkylene)-R⁹(where R⁹ is —COOH, —COR¹⁰, —COOR¹¹ or —CONR¹²R¹³) can be prepared froma compound of formula 5 as shown below:

[0246] A compound of Formula (I) where R³ is —O-(alkylene)-COOR¹¹ isprepared by reacting a compound of formula 5 with an alkylating agent offormula X-(alkylene)-CO₂R¹¹ where X is a halo group. Hydrolysis of theester group provides the free acid (R⁹ is —COOH) which can be convertedto a compound of Formula (I) where R⁹═—CONR¹²R¹³, if desired, bytreating the acid with an amine of formula NR¹²R¹³ (where R¹² and R¹³are as defined in the Summary of the Invention) in the presence of asuitable coupling agent (e.g., carbonyl diimidazole,N,N-dicyclohexylcarbodiimide and the like).

[0247] A compound of Formula (I) where R⁹ is —COR¹⁰ can be prepared froma compound of Formula (I) where R⁹ is —COOH by first converting the acidto a Weinreb amide followed by treatment with either a Grignard reagentor organolithium reagent of formula R¹⁰MgBr or R¹⁰Li, respectively.

[0248] (iii) Other compounds of Formula (I) where R³ is X(alkylene)CH[(CR′R″)_(m)OR⁴⁰] [(CR′R″)_(n)OR⁴⁰] {such as in Examples 26and 27 wherein X is —O—; R⁴⁰ is acyl or C(O)OR⁴¹ (where R⁴¹ is hydrogen,alkyl, or cycloalkyl); R′ and R″ are hydrogen; m is 0; and n is 1} canbe prepared by converting a compound of formula 5 to a bishydroxy alkoxyderivative (such as the diol of Example 24), followed by treatment withan anhydride R⁴⁰C(O)OC(O)R⁴⁰, an acid chloride R⁴⁰C(O)Cl, or achloroformate ester ClC(O)OR⁴¹.

[0249] Other compounds of Formula (I) where R³ is X(alkylene)CH[(CR′R″)_(m)OR⁴⁰] [(CR′R″)_(n)OR⁴⁰] {wherein X is —O—; R⁴⁰is C(O)NR⁴¹R⁴² (where R⁴¹ is hydrogen, alkyl, or cycloalkyl and R⁴² ishydrogen or alkyl); R′ and R″ are hydrogen; m is 0; and n is 1) can beprepared by converting a compound of formula 5 to a bishydroxy alkoxyderivative (such as the diol of Example 24), followed by treatment withan alkylcarbamoyl chloride R⁴¹R⁴²NC(O)Cl.

[0250] (iv) A compound of Formula (I) where R³ is —NH-(alkylene)-R⁹where R⁹ is —COOH, —COR¹⁰, —COOR¹¹, —CONR¹²R¹³ or heterocyclylalkylaminocan be prepared from a compound of formula 4 where Z is a nitro group byreducing the nitro group to the amino group and then following theprocedures described above.

[0251] (v) A compound of Formula (I) where R³ is heteroalkeny)heteroalkynyl, heterocyclylalkenyl, heterocyclylalkynyl, heteroalkyl orheterocyclylalkyl can be prepared as shown below.

[0252] A compound of Formula (I) where R³ is heteroalkenyl,heteroalkynyl, heterocyclylalkenyl or heterocyclylalkynyl can beprepared by reacting a compound of formula 4 where Z is halo with aheteroalkene, heteroalkyne, heterocyclylalkene or heterocyclylalkynerespectively in the presence of a palladium (II) catalyst such asdichlorobis(triphenylphosphine)palladium (II) in an organic base such asdiisopropylamine, and the like. Heteroalkenes, heteroalkynes such asallyl alcohol, propargyl alcohol, 3-butyn-1-ol, propargylamine arecommercially available. Heterocyclylalkyne can be prepared by reactingan alkynyl halide with a heterocycle. For example,2-morpholin-1-ylprop-1-yne can be prepared by reacting propargyl bromidewith morpholine. Reduction of the double or triple bond under catalytichydrogenation reaction conditions provides the corresponding compound ofFormula (I) where R³ is a heterocyclylalkyl or heteroalkyl group.

[0253] (vi) A compound of Formula (I) where R³ is —NHSO₂R⁶, —NHSO₂N⁷R⁸or NHC(X)R²³R²⁴ (where X is —O— or —S—) can be prepared from a compoundof Formula (I) where R³ is amino by following the synthetic proceduresdescribed in PCT Application No. WO 97/46524.

[0254] A compound of Formula (I) where R¹ is an acyl group can beprepared by reacting the the corresponding compound of Formula (I) whereR¹ is hydrogen with an acylating reagent of formula R¹COL where L is aleaving group under acylating reaction conditions such as halo. Thereaction is carried out in the presence of a base such as sodiumhydroxide, cesium carbonate, and the like.

[0255] Method (b)

[0256] Alternatively, a compound of Formula (I) can be prepared from anester of formula 6 where Z is as defined above, by first converting theZ group in compound 6 to the desired R³ group utilizing the reactionconditions described in method (a)(i-v) above. Condensation of 7 withacetonitrile anion gives a 2-ketoacetonitrile of formula 8 which is thenconverted to a compound of Formula (I) utilizing the reaction conditionsdescribed in method (a) above.

[0257] Compounds of Formula (I) where R² is thioalkyl or alkyl can beprepared by following the procedures described in U.S. Pat. No.5,712,303.

[0258] Condensation of 2-cyano-3-ethoxyacrylate of formula 9 with ahydrazine of formula 3 provides a 5-amino-4-ethoxycarbonyl pyrazole offormula 10. The condensation reaction is carried out in a suitable polarorganic solvent such as ethanol, isopropanol, and the like. Hydrolysisof 10 with an aqueous base (e.g., sodium hydroxide, lithium hydroxide,and the like) in an alcoholic organic solvent (e.g., methanol, ethanol,and the like) provides the corresponding 5-amino-4-carboxypyrazole offormula 11. Treatment of 11 with dipyridyldisulfide followed by reactionof the resulting thiopyridyl ester derivative 12 with an organometallicreagent such as a Grignard reagent or an organolithium reagent shownabove provides a compound of Formula (I).

Scheme C

[0259] Another alternate synthesis of compounds of Formula (I) where R²is hydrogen and other groups are as defined in the Summary of theInvention is described below.

[0260] Thermal decarboxylation of a 5-amino-4-carboxypyrazole of formula11 gives the corresponding 5-aminopyrazole of formula 13. Compound 13 isthen converted to a compound of Formula (I) as shown in method (a) or(b) above.

[0261] In method (a), a compound of formula 13 is converted to acompound of Formula (I) by first protecting the amino group in compound13 with a suitable amino protecting group (e.g., tert-butoxycarbonyl,and the like) to give the corresponding amino-protected compound offormula 14. Treatment of 14 with an acid derivative of formula R³COLwhere L is a leaving group under organometallic displacement reactionconditions [e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino,or preferably N,O-dimethylhydroxylamino] followed by the removal of theamino protecting group then provides a compound of Formula (I). Thenucleophilic substitution is carried out in the presence of 2equivalents of an alkyllithium (e.g., tert-butyllithium, and the like)and in an aprotic organic solvent such as tetrahydrofuran. The reactionconditions employed for the removal of the amino protecting groupdepends on the nature of the protecting group. For example, iftert-butoxycarbonyl is the protecting group, it is removed by treatmentwith an acid such as trifluroacetic acid, hydrochloric acid, and thelike.

[0262] Acid derivatives of formula R³COL can be prepared by methods wellknown in the field of organic chemistry. For example, an acid derivativewhere L is a N,O-dimethylhydroxylamino group can be prepared from itscorresponding acid by first converting the acid to the acid chloridewith a suitable chlorinating agent such as oxalyl chloride, followed bytreatment with N,O-dimethylhydroxylamine hydrochloride in the presenceof an organic base such as triethylamine.

[0263] In method (b), a compound of formula 10 is brominated to give the5-amino-4-bromopyrazole of formula 15. The bromination reaction iscarried out with a suitable brominating agent such as N-bromosuccinimidein a suitable polar organic solvent such as dimethylformamide. Compound15 is then converted to a compound of Formula (I) utilizing the reactionconditions described in Scheme C, method (a) above.

Utility, Testing, and Administration Utility

[0264] The compounds of Formula (I) are p38 MAP kinase inhibitors andtherefore compounds of Formula (I) and compositions containing them areuseful in the treatment of diseases such as rheumatoid arthritis,osteoarthritis, spondylitis, bone resorption diseases, sepsis, septicshock, toxic shock syndrome, endotoxic shock, tuberculosis,atherosclerosis, diabetes, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, fever, periodontal diseases, ulcerativecolitis, pyresis, Alzheimer's and Parkinson's diseases.

Testing

[0265] The ability of the compounds of Formula (I) to inhibit p38 MAPkinase was demonstrated by the in vitro assay described in Example 15.The ability of the compounds of Formula (I) to inhibit the release ofTNF-α was demonstrated by the in vitro and the in vivo assays describedin detail in Examples 16 and 17, respectively. The anti-inflammatoryactivity of the compounds of this invention was determined utilizingadjuvant induced arthritis in rats assay described in Example 18.

Administration and Pharmaceutical Compositions

[0266] In general, the compounds of this invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

[0267] Therapeutically effective amounts of compounds of Formula (I) mayrange from approximately 0.1-50 mg per kilogram body weight of therecipient per day; preferably about 1-30 mg/kg/day. Thus, foradministration to a 70 kg person, the dosage range would most preferablybe about 70 mg to 2.1 g per day.

[0268] In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

[0269] The choice of formulation depends on various factors such as themode of drug administration (e.g., for oral administration, formulationsin the form of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

[0270] The compositions are comprised of in general, a compound ofFormula (I) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound ofFormula (I). Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

[0271] Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

[0272] Compressed gases may be used to disperse a compound of thisinvention in aerosol form. Inert gases suitable for this purpose arenitrogen, carbon dioxide, etc.

[0273] Other suitable pharmaceutical excipients and their formulationsare described in Remington's Pharmaceutical Sciences, edited by E. W.Martin (Mack Publishing Company, 18th ed., 1990).

[0274] The amount of the compound in a formulation can vary within thefull range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of a compound of Formula (I) based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about 1-80wt %. Representative pharmaceutical formulations containing a compoundof Formula (I) are described in Example 14.

EXAMPLES

[0275] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. Numbers in brackets refer to the CPD # in Table I.

Example 15-Amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)prop-1-ynyl}benzoyl]pyrazole(3)

[0276]

[0277] Step 1

[0278] n-Butyllithium (214 ml, 340 mmol, 1.6 M solution in hexane) wasadded dropwise to a solution of acetonitrile (23.8 ml, 460 mmol) in drytetrahydrofuran (1000 ml) at −78° C. After stirring the reaction mixturefor 20 min., a solution of 4-bromobenzoyl chloride in drytetrahydrofuran (50 ml) was added dropwise over 20 min. After 1 h,saturated ammonium chloride was added (200 ml) and the reaction mixturewas allowed to warm to room temperature. The product was extracted intoether and washed with 1N hydrochloric acid (400 ml). The organics wereremoved in vacuo and the residue was redissolved in ethyl acetate.Ammonium hydroxide was added to give a solid which was filtered,redissolved in ethyl acetate and washed with 2N hydrochloric acid. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo to give 2-(3-bromobenzoyl)acetonitrile (16.6 g) asa solid.

[0279] Step 2

[0280] A mixture of 2-(3-bromobenzoyl)acetonitrile (16.5 g, 73.6 mmol)and N,N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 ml) washeated at reflux under a nitrogen atmosphere. After 3 h, the reactionmixture was cooled to room temperature and diluted with ether to give2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (17.9 g) as a solid.

[0281] Step 3

[0282] A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) inethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After4 h, the reaction mixture was cooled to room temperature, diluted withhexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole(9.7 g) as a solid.

[0283] Replacing 4-fluorophenylhydrazine with2,4-difluorophenylhydrazine in step 3 above gave5-amino-4-(3-bromobenzoyl)-1-(2,4-difluorophenyl)pyrazole.

[0284] Step 4

[0285] A mixture of5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.3 g, 4.16mmol), 4-(prop-2-ynyl)morpholine (2.1 g, 16.6 mmol) [prepared by addingto a solution of morpholine (14.7 ml, 168 mmol) in ether (50 ml),propargyl bromide (7.5 ml, 84 mmol) in ether (50 ml) dropwise over 30min. and heating the reaction mixture to reflux. After 16 h, thereaction mixture was cooled to room temperature and filtered through aBuchner funnel. The filtrate was concentrated and purified by flashchromatography (gradient elution, 20-100% EtOAc/hexane) to give4-(prop-2-ynyl)morpholine (5.0 g)], bis(triphenylphosphine)palladiumchloride (0.29 g, 0.42 mmol) and copper iodide (0.079 g, 0.42 mmol) indiisopropylamine (60 ml) was heated at 70° C. under argon. After 10 h,the reaction mixture was cooled to room temperature, diluted with ethylacetate, washed with brine and dried over sodium sulfate. The organicswere removed in vacuo. The crude product was purified by flashchromatography (elution gradient, EtOAc-5% MeOH/EtOAc with 0.2% NH₄OH)to give5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]-pyrazole which was converted to the hydrochloride salt andrecrystallized from a mixture of methanol/ethyl acetate/hexane to give(1.4 g) of the pure product.

[0286] Proceeding as described in Example 1 above but substituting4-(prop-2-ynyl)morpholine in Step 4 with:

[0287] 1-(prop-2-ynyl)-4-methylpiperazine,

[0288] 1-(prop-2-ynyl)piperidine,

[0289] 2-propyn-1-ol,

[0290] 1-dimethylamino-2-propyne, and

[0291] 2-methyl-3-butyn-2-ol; gave

[0292]5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]benzoyl}pyrazole.2HCl(8),

[0293]5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidin-1-yl)prop-1-ynyl}benzoyl]pyrazole.HCl(9),

[0294]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyprop-1-ynyl)benzoyl]pyrazole(7),

[0295]5-amino-4-[3-(3-dimethylaminoprop-1-ynyl)benzoyl]-1-(4-fluorophenyl)pyrazole.HCl(12), and

[0296]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)benzoyl]pyrazole(87), respectively.

[0297] Proceeding as described in Example 1 above but substituting4-fluorophenylhydrazine in Step 3 with 2,4-difluorophenylhydrazine, and4-(prop-2-ynyl)morpholine in Step 4 with 3-ethynylpyridine gave

[0298]5-amino-1-(2,4difluorophenyl)-4-[3-(3-pyridylethynyl)benzoyl]pyrazole(88),

[0299] with 3-(S,S-dioxo-thiomorpholin-4-yl)-1-propyne gave

[0300]5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)-1-propynyl}benzoyl]pyrazole(89), and

[0301] with 1-ethynylcyclopentanol gave

[0302]5-amino-1-(2,4-difluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl]benzoyl]pyrazole(94).

Example 25-Amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]-pyrazolehydrochloride (6)

[0303]

[0304] A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)-benzoyl]pyrazole(0.45 g, 1.0 mmol) [prepared as described in Example 1] and 5% Pd/C(0.07 g) in ethanol (20 ml) was stirred under hydrogen atmosphere. After16 h, the reaction mixture was filtered through Celite® and the filtratewas concentrated in vacuo. The crude product was purified by flashchromatography (elution gradient, EtOAc-15% MeOH/EtOAc with 0.2% NH₄OH).The product was converted to the hydrochloride salt and recrystallizedfrom a mixture of methanol/ethyl acetate to give5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.HCl(0.3 g, mpt. 211.9-212.6° C.) as a solid.

[0305] Proceeding as described in Example 2 above, but substituting of5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazolewith:

[0306]5-amino-1-(4-fluorophenyl)-4-{3[3-(4-methylpiperazin-1-yl)prop-1-ynyl}benzoyl]pyrazole,

[0307]5-amino-1-(4-fluorophenyl)-4-[3-{3-(piperidin-1-yl)prop-1-ynyl}benzoyl]pyrazole,

[0308]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxyprop-1-ynyl)benzoyl]pyrazole,

[0309]5-amino-4-[3-(3-dimethylaminoprop-1-ynyl)benzoyl]-1-(4-fluorophenyl)pyrazole,

[0310]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methyl-1-butynyl)benzoyl]pyrazole,

[0311]5-amino-1-(2,4-difluorophenyl)-4-[3-(3-pyridylethynyl)benzoyl]pyrazole,

[0312]5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)-1-propynyl}benzoyl]pyrazole,

[0313]5-amino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl}benzoyl]pyrazole,and

[0314]5-amino-1-(2,4-difluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethynyl}benzoyl]pyrazolegave

[0315]5-amino-1-(4-fluorophenyl)-4-{3-[3-(4-methylpiperazin-1-yl)propyl]benzoyl}pyrazole(30);

[0316]5-amino-1-(4-fluorophenyl)-4-[3-(3-piperidin-1-ylpropyl)benzoyl]pyrazole(32);

[0317]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxypropyl)benzoyl]pyrazole;

[0318]5-amino-4-[3-(3-dimethylaminopropyl)benzoyl]-1-(4-fluorophenyl)pyrazole;

[0319]5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methylbutyl)benzoyl]pyrazole(90),

[0320]5-amino-1-(2,4-difluorophenyl)-4-[3-(3-pyridylethyl)benzoyl]pyrazole(91),

[0321]5-amino-1-(2,4-difluorophenyl)-4-[3-{3-(S,S-dioxo-thiomorpholin-4-yl)propyl}benzoyl]pyrazole(92),

[0322]5-amino-1-(4-fluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethyl}benzoyl]pyrazole(93), and

[0323]5-amino-1-(2,4-dfluorophenyl)-4-[3-{2-(1-hydroxycyclopentyl)ethyl}benzoyl]pyrazole(94) respectively.

Example 35-Amino-1-(4-fluorophenyl)-4-[3-{2-(morpholin-4-yl)ethoxy}benzoyl]-pyrazolehydrochloride (14)

[0324]

[0325] Step 1

[0326] A mixture of methyl 3-hydroxybenzoate (8.0 g, 56 mmol) and4-(2-chloroethyl)morpholine hydrochloride (15.7 g, 84 mmol) andpotassium carbonate (11.5 g, 83 mmol) in toluene (50 ml) was heated atreflux. After 4 days, the reaction mixture was cooled to roomtemperature and diluted with ethyl acetate. The organic layer was washedwith water and then extracted with dilute hydrochloric acid. The acidiclayer was separated, basified with 5N sodium hydroxide and the productwas extracted into ethyl acetate. The organics were removed in vacuo andthe residue was purified by flash chromatography (elution gradient 3%acetone/methylene chloride) to give methyl3-(2-morpholin-4-ylethoxy)benzoate (9.0 g) as an oil.

[0327] Step 2

[0328] Lithium diisopropylamide (18.8 ml, 37 mmol, 2.0 M solution inheptane/tetrahydrofuran/ethylbenzene) was added dropwise to a solutionof acetonitrile (1.58 g, 37 mmol) in dry tetrahydrofuran (50 ml) at -78° C. After stirring the reaction mixture for 30 min., a solution ofmethyl 3-(2-morpholin4-ylethoxy)benzoate in dry tetrahydrofuran (50 ml)was added dropwise over 10 min. After 15 min., water was added and thereaction mixture was allowed to warm to room temperature. The aqueouslayer was separated and acidified with dilute hydrochloric acid to pH 7.The product was extracted into ethyl acetate and washed with water andbrine and dried over magnesium sulfate. The organics were removed invacuo to give 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g)as an oil which was used in the next step without further purification.

[0329] Step 3

[0330] A mixture of 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile(5.0 g) and N,N-diphenylformamidine (5.0 g, 25.5 mmol) in xylene (150ml) was heated at 100° C. under a nitrogen atmosphere. After 3 hr thereaction mixture was cooled to room temperature and diluted with hexaneto give 2-[3-(2-morpholin-4-ylethoxy)benzoyl]-3-phenylaminoacrylonitrile(5.0 g) as a solid.

[0331] Step 4

[0332] A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylaminoacrylonitrile (2.0g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogenatmosphere. After 6 h, the reaction mixture was cooled to roomtemperature and diluted with water. The product was extracted into ethylacetate and the organic layer was washed with brine, dried over sodiumsulfate and concentrated in vacuo. Purification by flash chromatography(elution gradient: CH₂Cl₂-3%MeOH/CH₂Cl₂) gave5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazolewhich was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5°C.).

[0333] Replacing 4-fluorophenylhydrazine in Step 4 above with:

[0334] 2-fluorophenylhydrazine, and

[0335] 2,6-dichlorophenylhydrazine, respectively were obtained:

[0336]5-amino-1-(2-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole(97), and

[0337]5-amino-1-(2,6-dichlorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole(98).

Example 4 5-Amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(20)

[0338]

[0339] Step 1

[0340] A mixture of5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (0.9 g, 2.5 mmol)[prepared as described in Example 1 above], pyridine-3-boronic acid,1,3-propanediol cyclic ester (0.5 g, 3 mmol), potassium phosphate (0.8g, 3.73 mmol) and tetrakistriphosphine palladium (0.3 g, 0.25 mmol) indioxane (20 ml) was heated at 85° C. under argon. After 16 h, thereaction mixture was cooled to room temperature and poured into brine.The product was extracted into ethyl acetate, dried over sodium sulfateand filtered. The organic layer was removed in vacuo and the residue waspurified by flash chromatography (elution gradient: 40-80% ethylacetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]-pyrazole (0.50 g)which was recrystallized from ethyl acetate (mpt. 222.2-223.0).

[0341] Treatment of5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]-pyrazole withmethyl iodide in ethyl acetate gave5-amino-1-(4-fluorophenyl)-4-[3-(N-methylpyridinium-3-yl)benzoyl]pyrazoleiodide (59).

[0342] Substitution of5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole with5-amino-4-(3-bromobenzoyl)-1-(2,4-difluorophenyl)pyrazole in Step 1above followed by conversion to the hydrochloride salt gave5-amino-1-(2,4-difluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.HCl(99).

Example 55-Amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(50)

[0343]

[0344] Step 1

[0345] A mixture of 5-amino4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole(1.5 g, 4.14 mmol) [prepared as described in Example 1 above],vinylsulfonamide (1.33 g, 12.4 mmol), bis(triphenylphosphine)palladiumchloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) indimethylformamide (18 ml) was heated at 100° C. under argon. After 16 h,the reaction mixture was cooled to room temperature and poured into 1 Nhydrochloric acid. The product was extracted into ethyl acetate, washedwith brine, dried over sodium sulfate and filtered. The organic layerwas removed in vacuo and the residue was purified by flashchromatography (elution gradient: 40-80% ethyl acetate/hexane) to give5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazolewhich was recrystallized from a mixture of methanol/ethyl acetate/hexaneto give 0.78 g of the desired product.

[0346] Step 2

[0347] A mixture of5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole(2.1 g, 5.43 mmol) and palladium hydroxide (0.6 g) in methanol (150 ml)was shaken in a Parr apparatus under hydrogen atmosphere at 50 psi.After 4 days, the reaction mixture was filtered through Celite® and thefiltrate was concentrated. The residue was purified by flashchromatography (elution gradient: 40-100% ethyl acetate/hexane) to givea crude product which was recrystallized from methanol/ethylacetate/hexane to give5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(0.95 g, mpt. 170-170.4° C.) as a solid.

[0348] Replacement of vinylsulfonamide in Step 1 above withvinylmethylsulfone gave:

[0349]5-amino-4-[3-(2-methylsulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole(100).

Example 65-Amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)-benzoyl]pyrazole(18)

[0350]

[0351] Step 1

[0352] A mixture of5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g, 9.7 mmol)[prepared as described in Example 1 above], tributyl-(1-ethoxyvinyl)tin(4.3 ml, 12.36 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g,0.87 mmol) in dimethylformamide (25 ml) was heated at 95° C. underargon. After 16 h, the reaction mixture was cooled to room temperatureand 10% aqueous hydrochloric acid (25 ml) was slowly added. After 30min., the reaction mixture was diluted with ethyl acetate and filteredthrough Celite®. The organic layer was separated and washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (elution gradient: 10-60% ethylacetate/hexane) to give5-amino-4-[3-(1-ethoxyvinyl)benzoyl]-1-(4-fluorophenyl)pyrazole whichwas dissolved in tetrahydrofuran (50 ml). 1 N hydrochloric acid (20 ml)was added and the reaction mixture was stirred at room temperature for16 h. The organic layer was separated, washed with brine, dried oversodium sulfate and concentrated in vacuo. The crude product was purifiedby flash chromatography (elution gradient: 20-50% ethyl acetate/hexane)and then was recrystallized from a mixture of ethyl acetate/hexane togive 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole (2.0 g).

[0353] Step 2

[0354] To a suspension of copper bromide (2.2 g, 9.85 mmol) in a (1:1)mixture of ethyl acetate/methylene chloride (100 ml) at reflux was addeda solution of 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole(1.6 g, 4.95 mmol) in methylene chloride (25 ml) under nitrogen. After16 h, the reaction mixture was concentrated and the residue waspartitioned between aqueous sodium bisulfite and ethyl acetate. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (elution gradient: 10-40% ethyl acetate/hexane) to give5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.47 g)as a solid.

[0355] Step 3

[0356] To a solution of morpholine (0.25 ml, 2.79 mmol) indimethylformamide (5 ml) was added a solution of5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.22 g,0.56 mmol) in dimethylformamide (5 ml). After 16 h, the reaction mixturewas poured into brine and the product was extracted into ethyl acetate.The organic layer was separated, washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (elution gradient: ethyl acetate-10% methanol/ethylacetate) to give5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)benzoyl]pyrazole(0.05 g) as a solid.

Example 75-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (118)

[0357]

[0358] Step 1

[0359] To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) intetrahydrofuran (100 ml) at 0° C. was added diborane (70 ml, 1.0 Msolution in tetrahydrofuran). The reaction mixture was allowed to warmto room temperature. After 16 h, the reaction mixture was cooled to 0°C. and water was added dropwise (50 ml). The organic layer was separatedand washed with brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by flash chromatography (elutiongradient: 40-60% ethyl acetate/hexane) to give3-(2-hydroxyethyl)bromobenzene (9.0 g).

[0360] Step 2

[0361] To a solution of 3-(2-hydroxyethyl)bromobenzene (4.0 g, 20 mmol)in methylene chloride (100 ml) at 0° C. was added a solution oftert-butyldimethylsilyl chloride (3.6 g, 24 mmol), dimethylaminopyridine(0.61 g, 5 mmol) and triethylamine (3.6 ml, 25.9 mmol). After 1 h, thereaction mixture was washed with brine, saturated ammonium chloride,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (elution gradient: 0-10% hexane/ethylacetate) to give 3-(2-tert-butyl-dimethylsiloxyethyl)bromobenzene (6.0g).

[0362] Step 3

[0363] A mixture of ethyl (ethoxymethylene)cyanoacetate (26 ml, 154mmol) and 4-fluorophenyl hydrazine (19.4 g, 154 mmol) in ethanol (125ml) was heated at reflux. After 16 h, the reaction mixture was cooled toroom temperature. The solid was filtered off and dried to give5-amino-4-ethylcarboxy-1-(4-fluorophenyl)pyrazole (28 g) which wassuspended in a mixture of 1 N lithium hydroxide (100 ml) and methanol(250 ml). The reaction mixture was heated at reflux. After 16 h, thereaction mixture was filtered through a sinter funnel and the filtratewas acidified with 2 N hydrochloric acid (65 ml). The solid was filteredoff and dried to give 5-amino-4-carboxy-1-(4-fluorophenyl)pyrazole (21g).

[0364] Step 4

[0365] A mixture of 5-amino-4-carboxy-1-(4-fluorophenyl)pyrazole (15 g,68 mmol), aldrathio]-2 (14.9 g, 68 mmol) and triphenylphosphine (17.8 g,68 mmol) in acetonitrile (21) was stirred at room temperature. After 16h, the product was filtered off and dried to give5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (14 g).

[0366] Step 5

[0367] Into an oven dried flask containing magnesium turnings (0.386 g,15.9 mmol) and tetrahydrofuran (10 ml) was added3-(2-tert-butyldimethylsiloxyethyl)bromobenzene (5.0 g, 15.9 mmol) andthe reaction mixture was heated at reflux. After 3 h, the reactionmixture was cooled to room temperature and5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (2.37 g, 7.6mmol) was added and the stirring was continued for 16 h. The reactionmixture was concentrated in vacuo. The residue was dissolved in ethylacetate and washed with aqueous ammonium chloride and brine and driedover sodium sulfate. The organics were removed in vacuo and the residuewas purified by flash chromatography (elution gradient: 10-30% ethylacetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethyl-siloxyethyl)benzoyl]pyrazole(1.20 g).

[0368] Step6

[0369] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)benzoyl]pyrazole(1.2 g, 3.0 mmol) in tetrahydrofuran (25 ml) was addedtetrabutylammonium fluoride (3.6 ml, 3.6 mmol, 1 M solution intetrahydrofuran). After 1 h, the reaction mixture was poured into brineand the product was extracted into ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatogaphy (elution gradient: 40-100%ethyl acetate/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8g).

Example 8 Synthesis of5-amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazin-1-yl)ethyl)benzoyl]pyrazoledihydrochloride (31)

[0370]

[0371] Step 1

[0372] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8 g,2.5 mmol) in pyridine (10 ml) was added methanesulfonyl chloride (0.29ml, 3.7 mmol). After 2 h, the reaction mixture was poured into 2 Nhydrochloric acid (40 ml) and the product was extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (elution gradient: 40-100% ethyl acetate/hexane) togive5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole(0.87 g).

[0373] Step 2

[0374] A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole(0.22 g, 0.55 mmol), N-methylpiperazine (0.18 ml, 1.64 mmol) andpotassium carbonate (0.22 g, 1.64 mmol) in dimethylformamide (10 ml) washeated at 70° C. After 4 h, the reaction mixture was cooled to roomtemperature, poured into water and the product was extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (elution gradient: ethyl acetate-20% methanol/ethylacetate) to5-amino-1-(4-fluorophenyl)-4-{3-[4-methylpiperazin-1-yl)ethyl)benzoyl]pyrazolewhich was converted to the hydrochloride salt (mpt. 272.9-273.9).

Example 9 5-Amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazolehydrochloride (47)

[0375]

[0376] Step 1

[0377] A mixture of5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole(0.40 g, 0.99 mmol), sodium azide (0.19 ml, 2.97 mmol) and potassiumcarbonate (0.41 g, 2.97 mmol) in dimethylformamide (15 ml) was stirredat room temperature. After 16 h, the reaction mixture was poured intobrine and the product was extracted into ethyl acetate. The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography (elution gradient:20-50% ethyl acetate/hexane) to5-amino-1-(4-fluorophenyl)-4-[3-(2-azidoethyl)benzoyl]pyrazole (0.32 g).

[0378] Step 2

[0379] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-(2-azidoethyl)benzoyl]pyrazole (0.31 g,0.9 mmol) in tetrahydrofuran (15 ml) was added triphenylphosphine (3.55g, 1.36 mmol). After 48 h, the reaction mixture concentrated in vacuo.The residue was dissolved in 2 N sodium hydroxide and the product wasextracted into ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The product was convertedto its hydrochloride salt and recrystallized from a mixture ofmethanol-ethyl acetate to give5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazolehydrochloride salt (0.22 g).

Example 105-Amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole

[0380]

[0381] Step 1

[0382] Into an oven dried flask containing magnesium turnings (0.408 g,17 mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17mmol) and the reaction mixture was heated at reflux. After 2 h, thereaction mixture was cooled to room temperature and5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5g, 4.8mmol) was added and the stirring was continued for 1 h. The reactionmixture was quenched with water and the product was extracted into ethylacetate. The organic layer was washed with aqueous ammonium chloride andbrine and dried over sodium sulfate. The organics were removed in vacuoand the residue was filtered and washed with hexane to give5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).

[0383] Step 2

[0384] To an ice-cooled solution of5-amino-1-(4-fluorophenyl)-4-(3-methoxybenzoyl)pyrazole (3.0 g, 10.0mmol) in methylene chloride (25 ml) was added boron tribromide (51 ml,51 mmol, 1 M solution in methylene chloride). After 1 h, the reactionmixture was poured into brine and the product was extracted into ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to give5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (2.4 g).

[0385] Step 3

[0386] A mixture of5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (1.0 g, 3.3mmol), tert-butyl bromoacetate (1.4 g, 7.2 mmol) and potassium carbonate(1 g, 7.2 mmol) in acetonitrile was heated at 70° C. overnight. Thereaction mixture was cooled, diluted with ethyl acetate and filtered.The filtrate was concentrated in vacuo and the residue was purified byflash chromatography (elution gradient: 10% acetone/hexane) to give5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole(1.2 g) as a solid.

Example 11

[0387] 5-Amino-4-[3-carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole(119)

[0388] Step 1

[0389] A mixture of5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole(1.0 g, 3.3 mmol) and trifluoroacetic acid (15 ml, 194 mmol ) inmethylene chloride (15 ml) was stirred overnight at room temperature.The organics were removed in vacuo and the residue was dissolved intoluene. The solution was concentrated and the residue was trituratedbetween ethyl acetate and hexane to give5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.8g) as a solid.

Example 125-Amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)benzoyl]pyrazole(34)

[0390]

[0391] Step 1

[0392] To a solution of5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.5g, 1.43 mmol) in tetrahydrofuran (10 ml) was added carbonyl diimidazole(0.3 g, 1.85 mmol) and the reaction mixture was heated at 60° C. After 1h, methylamine (10 ml, 5 mmol, 0.5 M solution in tetrahydrofuran) wasadded and reaction was continued at 60° C. overnight. The reactionmixture was cooled and diluted with ethyl acetate. The organic layer wasseparated and washed with brine and dried over sodium sulfate. Theorganics were removed in vacuo and the residue was purified by flashchromatography (elution gradient: 20-30% acetone/hexane) to give5-amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)benzoyl]pyrazole(0.25 g, mpt. 195.6-196.3° C.) as a solid.

[0393] Proceeding as described in Example 12 above, but substitutingmethylamine with: morpholine gave5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylcarbonylmethyloxy)benzoyl]pyrazole(35).

Example 135-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)propylamino}benzoyl]-pyrazole(48)

[0394]

[0395] Step 1

[0396] Benzoylacetonitrile (14.5 g, 10 mmol) was added to cold fumingnitric acid (50 ml) portionwise over 10 min. The reaction mixture wasstirred for 15 min., and then poured into ice. The solid was filteredoff and recrystallised from ethanol to give2-(3-nitrobenzoyl)acetonitrile (5.4 g) as a brown solid.

[0397] Step 2

[0398] A mixture of 2-(3-nitrobenzoyl)acetonitrile (13.75 g, 72.3 mmol)and N,N-diphenylformamidine (14.2 g, 72.3 mmol) in xylene (200 ml) washeated at reflux under nitrogen atmosphere. After 3 h, the reactionmixture was cooled to room temperature and diluted with xylenes to give2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (15.7 g) as a yellowsolid.

[0399] Step 3

[0400] A mixture of 4-fluorophenylhydrazine (2.24 g, 15.57 mmol) and2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (4.15 g, 14.16 mmol) inethanol (50 ml) was heated at reflux under nitrogen atmosphere. After 1h, the reaction mixture was cooled to room temperature and stirred foran additional 3 h. The solid was filtered and dried to give5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.5 g) as asolid.

[0401] Step 4

[0402] A mixture of5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.0 g, 24.52), Fepowder (3.84 g, 68 mmol) and ammonium chloride (3.84, 71.78 mmol) inethanol (135 ml) and water (64 ml) was heated at reflux under nitrogenatmosphere. After 1 h, the reaction mixture was cooled to roomtemperature and stirred overnight. The reaction mixture was filteredthrough Celite® and the filtrate was concentrated in vacuo. The residuewas partitioned between water and ethyl acetate. The organic layer wasseparated and washed with brine, dried over sodium sulfate andconcentrated in vacuo to give5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g) as asolid.

[0403] Step 5

[0404] 5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole (0.5 g, 1.6mmol), 1-bromo-3-chloropropane (0.26 g, 1.6 mmol) and cesium carbonate(0.52 g, 1.6 mmol) in dimethylformamide (25 ml) was heated at 80° C.After 2 days, the reaction mixture was cooled to room temperature anddiluted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (elution gradient: 20% acetone/hexanes)to give5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)pyrazole(0.2 g) as a solid.

[0405] Step 6

[0406] A mixture of5-amino-4-[3-(3-chloropropylamino)benzoyl]-1-(4-fluorophenyl)pyrazole(0.05 g, 0.13 mmol), morpholine (0.1 ml, 1.1 mmol), potassium carbonate(0.1 g) and potassium iodide (0.1 g) in acetonitrile (3 ml) was heatedat reflux. After 2 days, the reaction mixture was poured into brine andthe product was extracted into ethyl acetate. The organic layer wasseparated, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified by flash chromatography (elutiongradient: 3% MeOH/CH₂Cl₂) to give5-amino-1-(4-fluorophenyl)-4-[3-{3-(morpholin-4-yl)propylamino}-benzoyl]pyrazoleas a solid.

Example 145-amino-1-(4-fluorophenyl)-4-[3-{2-(piperidin-1-yl)ethoxy}benzoyl]pyrazoleHCl salt (81)

[0407]

[0408] Step 1

[0409] 5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, fromExample 10, step 2, 1.5 g, 5.05 mmol) was combined with toluene (50 mL).2-bromoethanol (1.79 mL, 25.23 mmol) was added and then the reactionmixture was cooled to 0° C. Triphenylphosphine (5.425 g, 20.69 mmol) anddiethyl azodicarboxylate (3.26 mL, 20.69 mmol) were then added. Thereaction was allowed to warm to room temperature. After stirring for 16hours, the reaction was quenched with a saturated aqueous solution ofNH₄Cl, extracted with ethyl acetate, dried (MgSO₄), filtered, andconcentrated under vacuum. The product(5-amino-1-(4-fluorophenyl)-4-[3-(2-bromoethoxy)benzoyl]pyrazole) waspurified by column chromatography on silica gel using 40:1 CH₂Cl₂/MeOHthen stirred with ether for 20 minutes, filtered and dried to give 0.785g of product.

[0410] Step 2

[0411] 5-amino-1-(4-fluorophenyl)-4-[3-(2-bromoethoxy)benzoyl]pyrazole(0.6 g, 1.48 mmol) was combined with piperidine (1.47 mL, 14.8 mmol) andethanol (10 mL) and heated at reflux for 16 hrs. The reaction mixturewas concentrated under vacuum. The resulting residue was partitionedbetween a saturated aqueous solution of NaHCO₃ and ethyl acetate andextracted three times with ethyl acetate. The organic extracts weredried (MgSO₄), filtered, concentrated under vacuum and purified bycolumn chromatography on silica gel using 16:1 CH₂Cl₂/NMeOH. Dissolvingthe product in ethyl acetate then adding hydrochloric acid (1.0 M, 1.0equivalent) formed the hydrochloric salt which was filtered and dried togive 0.413 g of5-amino-1-(4-fluorophenyl)-4-[3-{2-(piperidin-1-yl)ethoxylbenzoyl]pyrazole.HCl(mpt. 210.2-211.2° C.).

[0412] Proceeding as in Step 2 but replacing piperidine withdiethanolamine, dimethylamine, N-methylpiperazine, 2-aminoethanol,bis(2-methoxyethyl)amine, diethylamine, methylamine, ammonia, and3-oxopyridazine the following compounds were obtained. CPD HRMS MeltingCPD HRMS Melting Mole Structure # MW Point Mole Structure # MW Point

121 368.41 184.5-190

124 506.49 86.5-93.5

39 464.922 160.3-160.8

125 440.13 137.8-139.8

122 494.95 238.0-258.0

126 396.25 204.9-210.3

123 425.4 217.1-218.0

127 376.817 231.5-232.5

128 419.414 174.5-178.0

Example 155-amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole(82)

[0413]

[0414] 5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, fromExample 10, step 2, (0.5 g, 1.68 mmol), 2-pyridylcarbinol (0.81 mL, 8.41mmol), triphenylphospine (1.81 g, 6.9 mmol), and diethylazodicarboxylate(1.09 mL, 6.9 mmol)) were combined in toluene (50 mL). The reactionmixture was stirred for 16 hours then quenched with a saturated aqueoussolution of NH₄Cl and extracted three times with ethyl acetate. Theproduct was then extracted from the ethyl acetate into a 10% aqueoussolution of HCl. The aqueous layer was then neutralized with NaOH andextracted with ethyl acetate. The organic extracts were dried (MgSO₄),filtered, and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel using 1:1 hexane/ethyl acetate togive 0.165 g of5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole(mpt. 176.1-177.3° C.).

[0415] Replacing 2-pyridylcarbinol with glycolic acid,1-(2-hydroxyethyl)-2-pyrrolidinone and 4-hydroxypiperidine gave thefollowing compounds. Structure CPD # HRMS MWt M. Pt.

119 355.324 215.9-216.2

129 412.03

130 416.882 195.0-220.0

Example 165-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole(83)

[0416]

[0417] 5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, fromExample 10, step 2, (0.30 g, 1.01 mmol) was combined with K₂CO₃ (0.418g, 3.03 mmol) and THF (6 mL). The mixture was cooled in an ice bath andthen isopropyl isocyanate (0.12 mL, 1.21 mmol) was added. The reactionwas allowed to warm to room temperature and stirred for 16 hours. Thereaction mixture was quenched with water, extracted into ethyl acetate,dried (MgSO₄), filtered, and concentrated to dryness. The residue wasstirred in methanol and dichloromethane for one hour then filtered togive 0.118 g of5-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole(mpt. 225.2-230.1° C).

[0418] Replacing isopropyl isocyanate with ethyl isocyanate was made5-amino-1-(4-fluorophenyl)-4-[3-ethylaminocarbonyloxybenzoyl]pyrazole(84). Mpt. 201.2-202.8° C.

Example 17 5-Amino-1-(4-fluorophenyl)-4-[3-iodo benzoyl]pyrazole

[0419]

[0420] Step 1

[0421] n-Butyllithium (30.5 ml, 76 mmol, 2.5 M solution in hexane) wasadded dropwise to a cooled (0° C.) solution of diisopropylamine (10.6ml, 76 mmol) in 10 ml dry tetrahydrofuran. Once addition was complete,the solution was kept at 0° C. for 10 minutes and was then cooled to−50° C. This cold LDA solution was then added to a −50° C. solution ofacetonitrile (2.37 ml, 45.3 mmol) and ethyl 4-iodobenzoate (10.0 g, 36.2mmol) in dry tetrahydrofuran (18 ml). Once addition was complete, thereaction was stirred at −50° C. for 3 hours and was subsequently warmedto 0° C. Saturated ammonium chloride was added (20 ml) and the reactionmixture was allowed to warm to room temperature. The product wasextracted into ether mid washed with IN hydrochloric acid (50 ml). Theorganics were washed with brine (50 ml), dried over MgSO₄ and thenconcentrated in vacuo to a red oil. The oil was purified through a smallplug of silica gel using 3:1-2:1 hexanes/ethyl acetate as eluent.Concentration of the column fractions in vacuo gave2-(3-iodobenzoyl)-acetonitrile (8.3 g) as a yellow oil.

[0422] Step 2

[0423] A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol)and N,N-diphenylformamidine (26.2 g, 133.5 mmol) in toluene (200 ml) washeated at reflux under a nitrogen atmosphere. After 8 h, the reactionmixture was cooled to room temperature and diluted with ether (200 ml)to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as asolid.

[0424] Step 3

[0425] A mixture of 4-fluorophenylhydrazine (26.6 g, 211 mmol) and2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (79 g, 211 mmol) in ethanol(400 ml) was heated at reflux under a nitrogen atmosphere. After 30minutes, the reaction mixture was cooled to room temperature, dilutedwith hexane to give 5-amino-4-(3-iodobenzoyl)-1-(4-fluorophenyl)pyrazole(75.1 g) as a solid.

[0426] Replacing 4-fluorophenylhydrazine with 4-methylphenyllhydrazine,3-methoxyphenylhydrazine, 4-sulfamoylphenylhydrazine,2,4-dimethylphenylhydrazine, 2-methylphenylhydrazine,4-chloro-2-methylphenylhydrazine, 4-methylsulfonylphenylhydrazine,2-ethylphenylhydrazine, and 2,4-difluorophenylhydrazine in Step 3 abovegave respectively:

[0427] 5-amino-4-(3-iodobenzoyl)-1-(4-methylphenyl)pyrazole,

[0428] 5-amino-4-(3-iodobenzoyl)-1-(3-methoxyphenyl)pyrazole,

[0429] 5-amino-4-(3-iodobenzoyl)-1-(4-sulfamoylphenyl)pyrazole,

[0430] 5-amino-4-(3-iodobenzoyl)-1-(2,4-dimethylphenyl)pyrazole,

[0431] 5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole,

[0432] 5-amino-4-(3-iodobenzoyl)-1-(4-cloro-2-methylphenyl)pyrazole,

[0433] 5-amino-4-(3-iodobenzoyl)-1-(4-methylsulfonylphenyl)pyrazole,

[0434] 5-amino-4-(3-iodobenzoyl)-1-(2-ethylphenyl)pyrazol, and

[0435] 5-amino-4-(3-iodobenzoyl)-1-(2,4-difluorophenyl)pyrazole.

Example 185-amino-1-(4-fluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole(85)

[0436]

[0437] Step 1

[0438] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-iodobenzoyl]pyrazole (10 g, 24.6 mmol)in 100 ml dimethylformamide was added vinyltributytin (8.57 g, 27.0mmol) and tetrakistriphenylphosphine palladium (0) (1.42 g, 1.23 mmol).The resulting solution was degassed with argon and subsequently warmedto 100° C. for 12 hours

[0439] The reaction was cooled to room temperature and was poured into500 ml distilled water and was extracted 3×100 ml 1:1 ether/ethylacetate. The organics were washed with brine (150 ml), dried over MgSO₄and then concentrated in vacuo to a brown oil. The oil was purified byflash column chromatography using 5:1-4:1 hexanes/ethyl acetate toremove impurities and 3:1-2:1 hexanes/ethyl acetate to elute the desiredproduct. Concentration of the column fractions in vacuo gave5-amino-1-(4-fluorophenyl)-4-[3-vinylbenzoyl]pyrazole (4.48 g) as awhite solid.

[0440] Step 2

[0441] To a suspension of5-amino-1-(4-fluorophenyl)-4-[3-vinylbenzoyl]pyrazole (4.48 g, 13.95mmol) in 50 ml t-butanol was added N-methylmorpholine N-oxide (1.79 g,15.35 mmol) in 50 ml distilled water. To this mixture at roomtemperature was added a solution of 2.5% osmium tetraoxide in t-butanol(5.25 ml, 0.42 mmol). After 5 hours, the homogenous reaction was dilutedwith ethyl acetate (25 ml) and the organics were separated and washedwith brine (25 ml), dried over MgSO₄ and then concentrated in vacuo to abrown oil. The oil was purified by flash column chromatography using 1:1hexanes/ethyl acetate to remove impurities and ethyl acetate to elutethe desired product. Concentration of the column fractions in vacuo gave5-amino-1-(4-fluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole(4.48 g) as a white foam. The foam was triturated to a solid fromhexanes (2.36 g).

[0442] Replacing 5-amino-1-(4-fluorophenyl)-4-[3-iodobenzoyl]pyrazole inStep 1 above with:

[0443] 5-amino-1-(2,4-difluorophenyl)-4-[3-iodobenzoyl]pyrazole and

[0444] 5-amino-1-(2-methylphenyl)-4-[3-iodobenzoyl]pyrazole, gaverespectively

[0445]5-amino-1-(2,4-difluorophenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole(103) and

[0446]5-amino-1-(2-methylphenyl)-4-[3-(1,2-dihydroxyethyl)benzoyl]pyrazole(109).

Example 195-Amino-1-(2,4-difluorophenyl)-4-[3-(1-piperidinylmethyl)benzoyl]pyrazole(86)

[0447]

[0448] Step 1

[0449] To a suspension of 5-amino-1-(2,4-difluorophenyl)-4-[3-(1,2-dihydroxyethane)benzoyl]pyrazole (10.1 g, 28 mmol) in 100 mlt-butanol was added 100 ml distilled water and sodium periodate (18.06g, 84 mmol). After 2 hours, the solid precipitate was collected byvacuum filtration and was washed with 300 ml distilled water and driedin vacuo to give 8.28 g of5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl]pyrazole as a whitesolid.

[0450] Step 2

[0451] To a solution of5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl]pyrazole (0.3 g, 0.92mmol), piperidine (0.1 ml, 1.0 mmol), acetic acid (0.05 ml) in1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.29g, 1.37 mmol). After stirring at room temperature for 12 hours, thereaction was diluted with 10% hydrochloric acid and ethyl acetate (10ml). The aqueous layer was separated and neutralized to pH 9 with sodiumhydroxide and was then extracted with ethyl acetate. The combinedorganics were separated and washed with brine (25 ml), dried over MgSO₄and then concentrated in vacuo to a brown oil. The oil was purified byflash column chromatography using 1:1 hexanes/ethyl acetate to removeimpurities and ethyl acetate to elute the desired product. Concentrationof the column fractions in vacuo gave5-amino-1-(4-fluorophenyl)-4-[3-(1-piperidinylmethyl)benzoyl]pyrazole asan oil (0.211 g). The compound was triturated to a solid fromhexanes/ethyl acetate.

[0452] Replacing piperidine in Step 1 above with:

[0453] morpholine,

[0454] N-methylpiperazine,

[0455] 4-hydroxypiperidine,

[0456] 2-aminopyridine,

[0457] 3-aminopyridine,

[0458] 4-methylimidazole,

[0459] 3-aminopyrazole, and

[0460] 2-methylimidazole;

[0461] the following compounds were obtained CPD HRMS CPD HRMS Structure# MW MPt Structure # MW

131 398.411 127.3-128.5

135 405.406

132 484.376 238.2-238.6

136 393.395

133 412.438 141.5-145.5

137 508.405

134 405.406

138 507.417

Example 20 5-amino-1-(3-methylphenyl)-4-[3-{N-oxidopyridin-3-yl)}benzoyl]pyrazole (70)

[0462]

[0463] A mixture of5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole, from Example 17(0.98 g, 2.4 mmol), pinacol diboron (0.68 g, 2.7 mmol),[1,1′-bis(diphenylphoshino)ferrocene]dichloropalladium (0.2 g,.24 mmol)and potassium acetate (0.72 g, 7.3 mmol) in DMF (10 ml) was heated at 80degrees, under argon. After 2 h, the reaction mixture was cooled to roomtemperature and 3-bromopyridine N-oxide (0.47 g, 2.7 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.2 g, 0.24mmol) and 2 M sodium carbonate (6.1 ml, 12.2 mmol) was added and heatedto 80 degrees. After 16 h, the reaction mixture was cooled to roomtemperature, poured into brine and the product extracted into ethylacetate. The organic layer was dried over sodium sulfate, filtered andthen the solution was evaporated to dryness. The residue was purified byflash chromatography (gradient elution: ethyl acetate to 20%methanol/ethyl acetate) to give, after recrystallization frommethanol/ethyl acetate/hexane,5-amino-1-(3-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole(0.57 g, mpt. 190.5-191.2).

[0464] Replacing5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole/3-bromopyridineN-oxide with:

[0465]5-amino-4-(3-iodobenzoyl)-1-(4-methylphenyl)pyrazole/3-bromopyridine,

[0466]5-amino-4-(3-iodobenzoyl)-1-(3-methoxyphenyl)pyrazole/3-bromopyridine,

[0467]5-amino-4-(3-iodobenzoyl)-1-(4-sulfamoylphenyl)pyrazole/3-bromopyridine,

[0468]5-amino-4-(3-iodobenzoyl)-1-(2,4-dimethylphenyl)pyrazole/3-bromopyridine,

[0469]5-amino-4-(3-iodobenzoyl)-1-(2-methylphenyl)pyrazole/3-bromopyridine-N-oxide,

[0470] 5-amino-4-(3-iodobenzoyl)-1-(4-chloro-2-methylphenyl)pyrazole/3-bromopyridine,

[0471]5-amino-4-(3-iodobenzoyl)-1-(4-methylsulfonylphenyl)pyrazole/3-bromopyridine,

[0472]5-amino-4-(3-iodobenzoyl)-1-(2-ethylphenyl)pyrazole/3-bromopyridine, and

[0473]5-amino-4-(3-iodobenzoyl)-1-(2,4-difluorophenyl)pyrazole/2-bromoimidazole,

[0474] gave respectively the following compounds (as their hydrochloridesalts as appropriate):

[0475] 5-amino-1-(4-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(65),

[0476] 5-amino-1-(3-methoxyphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(66),

[0477] 5-amino-1-(4-sulfamoylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(68),

[0478]5-amino-1-(2,4-dimethylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (69),

[0479]5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole(70),

[0480]5-amino-1-(4-chloro-2-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(73),

[0481]5-amino-1-(4-methylsulfonylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(75),

[0482] 5-amino-1-(2-ethylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole(76), and

[0483]5-amino-1-(2,4-difluorophenyl)-4-[3-(imidazol-2-yl)benzoyl]pyrazole(77).

Example 215-amino-1-(2,4-difluorophenyl)-4-[N-oxidopyridin-3-yl)benzoyl]pyrazole(60)

[0484]

[0485] To a solution of5-amino-1-(2,4difluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole (4.6g, 12.2 mmol) in dichloromethane (100 ml) was added3-chloroperoxybenzoic acid (5.6 g, 18.3 mmol) and the mixture wasstirred at room temperature. After 4 h, a solution of 10% aqueous sodiumsulfite (50 ml) was added. After 0.5 h, the organic layer was separted,washed with brine, dried over sodium sulfate and filtered. The filtratewas concentrated to dryness and the residue purified by flashchromatography (gradient elution: ethyl acetate to 30% methanol/ethylacetate)to give, after recrystalliztion from methanol, 5-amino-1-(2,4-difluorphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole (1.3 g,Mpt. 251.1-251.7° C.).

Example 225-amino-1-(2,4-difluorophenyl)-4-[pyridin-4-yl)benzoyl]pyrazole (61)

[0486]

[0487] A mixture of5-amino-4-(3-bromobenzoyl)-1-(2.4-difluorophenyl)pyrazole (0.93 g, 2.5mmol), 4-tributylstannylpyridine (1.0 g, 2.7 mmol) andbis(triphenylphosphine)palladium chloride (0.17 g, 2.5 mmol) in DMF (15ml) was heated at 100 degrees under argon. After 16 h, the reactionmixture was cooled to room temperature and a solution of 10% aqueouspotassium flouride (30 ml) was added. After 1 h, the reaction mixturewas poured into brine, extracted with ethyl acetate, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby flash chromatography (gradient elution: 50-100% ethyl acetate/hexaneto 5% methanol/ethyl acetate to give, after recrystallizaion frommethanol/ethyl acetate,5-amino-1-(2,4-difluorophenyl)-4-[3-(pyridin-4-yl)benzoyl]pyrazole (0.42g, Mpt. 218-226° C.).

Example 235-Amino-1-(2,4-dimethylphenyl)-4-[3-(pyridin-3-yl)benzoylpyrazole HClsalt (69)

[0488]

[0489] Step 1

[0490] Into a solution of n-butyl lithium (165 ml, 264 mmol) in butylether (250 ml) at −78 degrees under nitrogen was added 3-bromopyridine(25.4 ml, 264 mmol). After 1 h, added diethylmethoxyborane (52 ml, 396mmol). The mixture was allowed to warm to room temperature. After 16 h,added water and brine, separated organic layer, dried over sodiumsulfate, then concentrated. The resulting slurry was dissolved inisopropanol (500 ml), cooled and the product isolated by filtration givediethyl(3-pyridyl)borane (29.8 g).

[0491] Step 2

[0492] A mixture of diethyl(3-pyridyl)borane (176.4 g, 1.2 mole),methyl-3-iodobenzoate(262 g, 1 mole), potassium phosphate (318.4 g, 1.5mole) and tetrakistriphenlyphosphine palladium (0) (57.8 g, 0.05 mole)in DMF (1000 ml) was heated at 80 degrees under argon. After 10 h, themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was filtered and washed with water. To the organicfraction was added concentrated HCL (65 ml). The organic layer wasseparated and extracted with aqueous HCl. The combined acid extractionswere treated with ethyl acetate, followed by 50% aqueous sodiumhydroxide (55 ml). The organic layer was separated, washed with waterand saturated sodium bicarbonate solution, then dried over sodiumsulfate. The solution was filtered and concentrated to givemethyl-3-(pyridin-3-yl)benzoate (145.3 g).

[0493] Step 3

[0494] To a solution of methyl-3-(pyridin-3-yl)benzoate (126.2 g, 0.59mole) in THF (600 ml) was added acetonitrile (37 ml, 0.71 mole) and thereaction was cooled to −40 degrees. A solution of lithium diisopropylamide (590 ml, 1.18 mole) was added dropwise. After 30 minutes, addedmethanol (25 ml) and after another 30 minutes, added water (110 ml).Allowed the reaction mixture to warm to 10 degrees and added ethylacetate. The layers were separated and the aqueous layer was acidifiedwith 1 M HCl. The aqueous layer was extracted with ethyl acetate,diluted with hexane and washed with brine. The organic phase wasconcentrated, then combined with N,N′-diphenylformanidine (120 g, 0.61mole) in 800 ml of ethyl acetate. The mixture was stirred at roomtemperature. After 3 days, the product was collected by filtration andrecrystallized from isopropanol, hexane to give2-(3-pyridin-3-yl)phenyl-3-phenylacrylonitrile (100 g).

[0495] Step 4

[0496] A solution of 2-(3-pyridin-3-ylphenyl)-3-phenylacrylonitrile (1.0g, 3 mmol) and 2,4-dimethyphenylhydrazine (0.4 g, 3 mmol) in ethanol (30ml) was heated at reflux, under nitrogen. After 6 h, the reaction wascooled to room temperature, concentrated to dryness and the residuepurified by flash column chromatography (elution gradient:40-100% ethylacetate/hexane to 10% methanol/ethyl acetate). The purified residue wastaken up in ethyl acetate and HCl/ether added to prepare the salt. Afterrecrystallization from methanol/ethyl acetate was isolated5-amino-1-(2,4dimethylphenyl)-4-[3-(pyridin-3-yl)benzoylpryrazolehydrochloride salt (0.74 g, m.pt. 250.7-251.8).

[0497] Proceeding as above in Example 23, but replacing2,4-dimethyphenylhydrazine in step 4 with:

[0498] phenylhydrazine,

[0499] 2-methyl-4-chlorophenylhydrazine,

[0500] 4-methoxyphenylhydrazine,

[0501] 4-methylsulfonylphenylhydrazine,

[0502] 2-ethylphenylhydrazine,

[0503] 4-isopropylphenylhydrazine,

[0504] 2-methoxyphenylhydrazine,

[0505] 3-chloro-4-methylphenylhydrazine,

[0506] 3-fluorophenylhydrazine, and

[0507] 3-fluoro-6-methylphenylhydrazine respectively, the followingcompounds were obtained. CPD HRMS CPD HRMS Mole Structure # MW MoleStructure # MW

139 376.845

141 418.926

73 425.317

142 406.871

140 406.871

143 425.317

75 454.936

144 394.835

76 404.899

145 408.862

Example 245-amino-1-(4-fluorophenyl)-4-[3-{2(R),3-dihydroxypropoxy}benzoyl]pyrazole(106)

[0508]

[0509] Step 1

[0510] To a solution of5-amino-4-(3-hydroxybenzoyl)-1-(4-fluorophenyl)pyrazole (0.5 g, 1.68mmol) in 5 ml dry dimethylformamide was addedD-α,β-isopropylideneglycerol-γ-tosylate (0.72 g, 2.52 mmol) followed byanhydrous potassium carbonate (0.695 g, 5.04 mmol). The reation waswarmed to 80° C. under argon. After 24 hours, the reaction was cooled toroom temperature and an additional 500 mg ofD-α,β-isopropylideneglycerol-γ-tosylate was added and the reaction waswarmed back to 80° C. under argon. After 8 additional hours, thereaction was cooled to room temperature and diluted with distilled water(50 ml) and the product was extracted into ether. The combined organicswere washed with brine (50 ml), dried over MgSO₄ and then concentratedin vacuo to a yellow oil. The oil was purified by flash columnchromatography on silica gel using 2:1-1:1 hexanes/ethyl acetate aseluent. Concentration of the column fractions in vacuo gave 556 mg ofthe desired acetal.

[0511] Step 2

[0512] To a solution of the acetal formed above (0.556 g, 1.35 mmol) inmethanol (10 ml) was added distilled water (2 ml) and p-toluenesulfonicacid monohydrate (5 mg). The solution was warmed to 80° C. under anargon atmosphere. After 2 h, the reaction mixture was cooled to roomtemperature concentrated in vacuo to a yellow oil which was redissolvedin ethyl acetate (50 ml) and saturated sodium bicarbonate (50 ml). Theorganic layer was separated, dried over MgSO₄ and then concentrated invacuo to a white solid. Recrystallization from hexanes/ethyl acetategave 196 mg of the desired diol (Mpt. 150.2-153.0° C.).

Example 255-amino-1-(4-fluorophenyl)-4-{3-[(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methoxy]benzoyl}pyrazole(170)

[0513]

[0514] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxyl}benzoyl]pyrazole(0.6 g, 1.6 mmol) in 30 ml acetone was added zinc chloride (0.34 g, 2.6mmol). The reaction mixture was stirred and heated at reflux. After 13hours, the reaction mixture was concentrated to dryness and the productwas purified by flash column chromatography on silica gel using 40%EtOAc/Hexane as elutent. The product was stirred with 1:1 ether/hexaneand 125 mg of 5-amino-1-(4-fluorophenyl)4-{3-[(2,2-dimethyl-1,3-dioxolan-5(S)-yl)methoxy]benzoyl}pyrazole wasobtained.

[0515] Proceeding as described above, but replacing acetone with thefollowing:

[0516] 3-pentanone and

[0517] methylethyl ketone,

[0518] gave the following compounds, respectively:

[0519]5-amino-1-(4-fluorophenyl)-4-{3-[(2,2-diethyl-1,3-dioxolan-4(S)-yl)methoxy]benzoyl}pyrazole (173) and

[0520]5-amino-1-(4-fluorophenyl)-4-{3-[(2-methyl-2-ethyl-1,3-dioxolan-4(S)-yl)methoxylbenzoyl}pyrazole (174).

Example 265-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(diacetoxy)propoxylbenzoyl]pyrazole(165)

[0521]

[0522] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxy)}benzoyl]pyrazole(1 g, 2.7 mmol) in pyridine (5 ml) was added acetic anhydride (0.5 ml,5.4 mmol) and DMAP (0.066 g, 0.5 mmol), and the reaction was stirred atroom temperature. After 16 h, the reaction mixture was poured intobrine, extracted with EtOAc, dried over sodium sulfate, concentrated todryness, and purified by flash chromatography (gradient elution, 20-60%EtOAc/Hexane). The product was recrystrallized from EtOAc/Hexane toafford 0.75 g of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(diacetoxy)propoxy}benzoyl]pyrazole.

[0523] Proceeding as described above, but replacing acetic anhydridewith the following:

[0524] isobutanoyl chloride and

[0525] pivaloyl chloride

[0526] gave the following compounds, respectively:

[0527]5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(diisobutanoyloxy)propoxy}benzoyl]pyrazole(166) and

[0528]5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(dipivaloyloxy)propoxy}benzoyl]pyrazole(167).

Example 275-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(dimethoxycarbonyloxy)propoxy}benzoyl]pyrazole(168)

[0529]

[0530] To a solution of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxyl}benzoyl]pyrazole(1 g, 2.7 mmol) in pyridine (5 ml) was added methyl chloroformate (2 ml,25.4 mmol). After 4 days, the reaction mixture was poured into brine,extracted with EtOAc, dried over sodium sulfate and concentrated todryness. The residue was purified by flash chromatography (gradientelution, 40-80% EtOAc/Hexane) to afford 0.55 g of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-(dimethoxycarbonyloxy)propoxy}benzoyl]pyrazole.

Example 285-amino-1-(4-fluorophenyl)-4-{3-[(1,3-dioxolan-2-on-4(R)-yl)methoxy]benzoyl}pyrazole(171)

[0531]

[0532] To a suspension of 15.0 g (40.4 mmol) of5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxyproxy}benzoyl]pyrazolein 150 ml THF was added 17 ml (168 mmol) of triethylamine. The mixturewas cooled to −5° C. and 18 ml of phosgene (20% in toluene) was addedover a 30 minute period keeping the reaction temperature below 0° C.Once addition was complete, the reaction was stirred for an additionalhour at 0° C. Then, 20 ml of distilled water was added along with 5% HCluntil the pH of the solution was 5 to 6. After 30 minutes, ethyl acetatewas added and the organic layer was separated, washed with brine, anddried over MgSO₄. Filtration and concentration in vacuo gave a yellowoil which was purified by flash column chromatography using 1:1-1:2hexanes/ethyl acetate as eluent. The desired carbonate precipitated uponconcentrating the column fractions to give 7.38 g of desired product.

Example 29 5-amino-1-(4-fluorophenyl)-4-thenoyl-pyrazole (114)

[0533]

[0534] Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-thenoyl)acetonitrile and thenfollowing step 3 was obtained5-amino-1-(4-fluorophenyl)-4-(2-thenoyl)-pyrazole.

[0535] Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-furanoyl)acetonitrile and thenfollowing step 3 was obtained5-amino-1-(4-fluorophenyl)-4-(2-furanoyl)-pyrazole (115).

[0536] Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(2-methyl-3-furanoyl)acetonitrileand substituting 4-fluorophenylhydrazine in step 3 with2,4-difluorophenylhydrazine was obtained5-amino-1-(2,4-difluorophenyl)-4-(2-methylfuran-3-oyl)-pyrazole (116).

[0537] Proceeding as described in Example 1, step 2, but replacing2-(3-bromobenzoyl)acetonitrile with 2-(6-quinolinoyl)acetonitrile andsubstituting 4-fluorophenylhydrazine in step 3 with2,4-difluorophenylhydrazine was obtained5-amino-1-(2,4-difluorophenyl)-4-(6-quinolinoyl)-pyrazole.HCl (117)(mpt. 220-259.2).

Example 30

[0538] The following are representative pharmaceutical formulationscontaining a compound of Formula (I). Tablet formulation The followingingredients are mixed intimately and pressed into single scored tablets.Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5Capsule formulation The following ingredients are mixed intimately andloaded into a hard-shell gelatin capsule. Quantity per Ingredientcapsule, mg compound of this invention 200 lactose, spray-dried 148magnesium stearate 2

[0539] Suspension formulation The following ingredients are mixed toform a suspension for oral administration. Ingredient Amount compound ofthis invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methylparaben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol(70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035ml colorings 0.5 mg distilled water q.s. to 100 ml Injectableformulation The following ingredients are mixed to form an injectableformulation. Ingredient Amount compound of this invention 0.2 g sodiumacetate buffer solution, 0.4M 2.0 ml HCl (1N) or NaOH (1N) q.s. tosuitable pH water (distilled, sterile) q.s. to 20 ml

[0540] All of the above ingredients, except water, are combined andheated to 60-70° C. with stirring. A sufficient quantity of water at 60°C. is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. to 100 g.

Suppository Formulation

[0541] A suppository of total weight 2.5 g is prepared by mixing thecompound of the invention with Witepsol® H-15 (triglycerides ofsaturated vegetable fatty acid; Riches-Nelson, Inc., New York), and hasthe following composition: compound of the invention 500 mg Witepsol ®H-15 balance

Example 31 Inhibition Of p-38 (MAP) Kinase . . . In Vitro Assay

[0542] The p-38 MAP kinase inhibitory activity of compounds of thisinvention in vitro was determined by measuring the transfer of theγ-phosphate from γ-³³P-ATP by p-38 kinase to Myelin Basic Protein (MBP),using the a minor modification of the method described in Ahn, N. G.; etal. J. Biol. Chem. Vol. 266(7), 4220-4227, (1991).

[0543] The phosphorylated form of the recombinant p38 MAP kinase wasexpressed with SEK-1 and MEKK in E. Coli and then purified by affinitychromatography using a Nickel column.

[0544] The phosphorylated p38 MAP kinase was diluted in kinase buffer(20 mM 3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 mM β-glycerolphosphate, 5 mM ethylene glycol-bis(beta-aminoethylether)-N,N,N′,N′-tetraacetic acid, 1 mM sodium vanadate, 1 mMdithiothreitol, 40 mM magnesium chloride). Test compound dissolved inDMSO or only DMSO (control) was added and the samples were incubated for10 min at 30° C. The kinase reaction was initiated by the addition of asubstrate cocktail containing MBP and γ-³³P-ATP. After incubating for anadditional 20 min at 30° C., the reaction was terminated by adding 0.75%phosphoric acid. The phosphorylated MBP was then separated from theresidual γ-³³P-ATP using a phosphocellulose membrane (Millipore,Bedford, Mass.) and quantitated using a scintillation counter (Packard,Meriden, Conn.).

[0545] Compounds of the invention were active in this assay. The p-38inhibitory activities (expressed as IC₅₀, the concentration causing 50%inhibition of the p-38 enzyme being assayed) of some compounds of theinvention are: CPD # IC₅₀, μM CPD # IC₅₀, μM 1 1.81 19 1.45 2 3.29 212.18 3 1.78 27 2.72 4 6.18 33 1.12 6 1.74 38 6.31 9 1.32 43 6.52 14 1.27 50 1.25

Example 32 Inhibition of LPS-Induced TNF-α Production In THP1 Cells . .. In Vitro Assay

[0546] The ability of the compounds of this invention to inhibit theTNF-α release was determined using a minor modification of the methodsdescribed in described in Blifeld, C. et al. Transplantation, Vol.51(2), 498-503, (1991).

[0547] (a) Induction of TNF biosynthesis

[0548] THP-1 cells were suspended in culture medium [RPMI (Gibco-BRL,Gailthersburg, Md.) containing 15% fetal bovine serum, 0.02 mM2-mercaptoethanol], at a concentration of 2.5×10⁶ cells/ml and thenplated in 96 well plate (0.2 ml aliquots in each well). Test compoundswere dissolved in DMSO and then diluted with the culture medium suchthat the final DMSO concentration was 5%. 20 μl aliquots of testsolution or only medium with DMSO (control) were added to each well. Thecells were incubated for 30 min., at 37° C. LPS (Sigma, St. Louis, Mo.)was added to the wells at a final concentration of 0.5 μg/ml, and cellswere incubated for an additional 2 h. At the end of the incubationperiod, culture supernatants were collected and the amount of TNF-αpresent was determined using an ELISA assay as described below.

[0549] (b) ELISA Assay

[0550] The amount of human TNF-α present was determined by a specifictrapping ELISA assay using two anti-TNF-α antibodies (2TNF-H22 and2TNF-H34) described in Reimund, J. M., et al. GUT. Vol. 39(5), 684-689(1996).

[0551] Polystyrene 96-well plates were coated with 50 μl per well ofantibody 2TNF-H22 in PBS (10 μg/ml) and incubated in a humidifiedchamber at 4° C. overnight. The plates were washed with PBS and thenblocked with 5% nonfat-dry milk in PBS for 1 hour at room temperatureand washed with 0.1% BSA (bovine serum albumin) in PBS.

[0552] TNF standards were prepared from a stock solution of humanrecombinant TNF-α (R&D Systems, Minneapolis, Minn.). The concentrationof the standards in the assay began at 10 ng/ml followed by 6 half logserial dilution's.

[0553] 25 gl aliquots of the above culture supernatants or TNF standardsor only medium (control) were mixed with 25 μl aliquots of biotinylatedmonoclonal antibody 2TNF-H34 (2 μg/ml in PBS containing 0.1% BSA) andthen added to each well. The samples were incubated for 2 h at roomtemperature with gentle shaking and then washed 3 times with 0.1% BSA inPBS. 50 μl of peroxidase-streptavidin (Zymed, S. San Francisco, Calif.)solution containing 0.416 μg/ml of peroxidase-streptavidin and 0.1% BSAin PBS was added to each well. The samples were incubated for anadditional 1 h at room temperature and then washed 4 times with 0.1% BSAin PBS. 50 μl of O-phenylenediamine solution (1 μg/mlO-phenylene-diamine and 0.03% hydrogen peroxide in 0.2 M citrate bufferpH 4.5) was added to each well and the samples were incubated in thedark for 30 min., at room temperature. Optical density of the sample andthe reference were read at 450 nm and 650 nm, respectively. TNF-α levelswere determined from a graph relating the optical density at 450 nm tothe concentration used. The IC₅₀ value was defined as the concentrationof the test compound corresponding to half-maximal reduction in 450 nmabsorbance. Compounds of the invention were active in this assay. Theactivity of selected compounds is shown below. CPD # IC₅₀, μM CPD #IC₅₀, μM 1 1.77 21 0.61 2 6.30 27 0.83 4 1.26 33 0.14 6 1.04 38 0.69 10 1.62 43 0.17 13  0.77 50 0.51 19  0.17

Example 33 Inhibition of LPS-Induced TNF-α Production In Rats . . . InVivo Assay

[0554] The ability of the compounds of this invention to inhibit theTNF-α release, in vivo, was determined using a minor modification of themethods described in described in Zanetti, G.; Heumann, D., et. al.,“Cytokine production after intravenous or peritoneal Gram-negativebacterial challenge in mice,” J. Immunol., 148, 1890, (1992) and Sekut,L., Menius, J. A., et. al., “Evaluation of the significance of elevatedlevels of systemic and localized tumor necrosis factor in differentanimal models of inflammation,” J. Lab. Clin. Med., 124, 813, (1994).

[0555] Female Sprague-Dawley rats weighing 110-140 grams (Charles River,Hollister, Calif.) were acclimated for one week. Groups containing 8mice each were dosed orally either with the test compounds dissolved inan aqueous vehicle containing 0.9% sodium chloride, 0.5% sodiumcarboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMCvehicle) or only vehicle (control group). After 30 min., the mice wereinjected intraperitoneally with 50 μg/kg of LPS (Sigma, St. Louis, Mo.).After 1.5 h, the mice were sacrificed by CO₂ inhalation and blood washarvested by cardiocentesis. Blood was clarified by centrifugation at15,600×g for 5 min., and sera were transferred to clean tubes and frozenat −20° C. until analyzed for TNF-α by ELISA assay (BiosourceInternational, Camarillo, Calif.) following the manufacturer's protocol.

[0556] The TNF-α inhibitory activity of selected compounds of theinvention, i.e., the measure of the TNF-α content in the test grouprelative to the vehicle treated group (control group) at 30 mg was: CPD% CPD % # Inhibition # Inhibition 3 96 19 76 8 86 34 75 16  86

Example 34 Adjuvant Arthritis Assay In Rats . . . In Vivo assay

[0557] The Anti-inflammatory activity of the compounds of this inventionwas determined utilizing adjuvant induced arthritis in rats. Briefly,Female Sprague Dawley rats, weighing 120-155 g (Charles River,Hollister, Calif.) were acclimated in-house for approximately 1 weekprior to use. On day 1, the animals were injected intradermally in the ¼proximal portion of the tail with 0.1 ml of a mineral oil (Sigma, St.Louis, Mo.) suspension of heat killed and dried Mycobacterium Butyricum(Difco, Bacto., Des., Lot 115979JAIEXP9/99) at a concentration of 1mg/0.1 ml.

[0558] On day 7, the test compounds were administered in CMC vehiclethrough to day 18. On day 18, following the administration of thecompound, animals were weighed. Clinical scores were obtained toevaluate the intensity of edema in the four paws and tail. A score of 0to 4 was assigned to each paw and 0 to 3 to the tail such that themaximum score was 19. Polyarthritic animals were scored 0 when noinflammatory signs ( swelling and redness) were observed in any of thesmall joints (intraphalangeal, metacarpophalangeal, metatarsophalangeal)or large joints (wrist/carpus, ankle/tarsus). Animals were scored 1 whenslight inflammation was observed, 2 moderate edema, 3 severe edema, and4 when very severe edema was present. The tail was scored 0 when nosigns of edema or necrotic tissue was observed, I when inocula injectionsites and immediate surrounding tissue exhibit slight edema, 2 whenapproximately ¼ of the tail was either inflamed or exhibiting necrotictissue, and 3 when over ¼ of the tail exhibited severe necroses oredema. Following clinical scores, the hind paws were transected at thedistal tibia, just proximal to the tarsal joint. The left and right hindpaws were weighed individually, and recorded.

[0559] The compounds of the present invention exhibit anti-inflammatoryactivity when tested in this assay.

[0560] The foregoing invention has been described in some detail by wayof illustration and example, for purposes of clarity and understanding.It will be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

[0561] All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed:
 1. A compound selected from the group of compoundsrepresented by Formula (I):

wherein: R¹ is hydrogen or acyl; R² is hydrogen or alkyl; A is an arylor heteroaryl ring; B is an aryl or heteroaryl ring; R³ is selected fromthe group consisting of: (a) amino, alkylamino or dialkylamino; (b)acylamino; (c) optionally substituted heterocyclyl; (d) optionallysubstituted aryl or heteroaryl; (e) heteroalkyl; (f) heteroalkenyl; (g)heteroalkynyl; (h) heteroalkoxy; (i) heteroalkylamino; (j) optionallysubstituted heterocyclylalkyl; (k) optionally substitutedheterocyclylalkenyl; (l) optionally substituted heterocyclylalkynyl; (m)optionally substituted cycloalkoxy, cycloalkylalkyloxy,heterocyclylalkoxy, or heterocyclyloxy; (n) optionally substitutedheterocyclylalkylamino; (o) optionally substitutedheterocyclylalkylcarbonyl; (p) heteroalkylcarbonyl; (q) optionallysubstituted cycloalkylamino; (r) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkylor optionally substituted heterocyclylalkyl; (s) —NHSO₂NR⁷R⁸ where R⁷and R⁸ are, independently of each other, hydrogen, alkyl or heteroalkyl;(t) —Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —N— or —S(O)_(n)—(where n is an integer from 0 to 2); and R⁹ is cyano, optionallysubstituted heteroaryl, —COOH, —COR¹⁰, —COOR¹¹, —CONR12R¹³, —SO₂R¹⁴,—SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl oroptionally substituted heterocycle, R¹¹ is alkyl, and R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independently of each other, hydrogen,alkyl or heteroalkyl; (u) C(═NR²⁰)(NR²⁰R²²) where R²⁰, R²¹ and R²²independently represent hydrogen, alkyl or hydroxy, or R²⁰ and R²¹together are —(CH₂)_(n)— where n is 2 or 3 and R²² is hydrogen or alkyl;(v) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴ are,independently of each other, hydrogen, alkyl or heteroalkyl; (w)—CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen, alkyl,heteroalkyl or optionally substituted heterocyclylalkyl, or R²⁵ and R²⁶together with the nitrogen to which they are attached form an optionallysubstituted heterocyclyl ring; (x) —S(O)_(n)R²⁷ where n is an integerfrom 0 to 2, and R²⁷ is alkyl, heteroalkyl, optionally substitutedcycloalkyl, optionally substituted heterocyclylalkyl, or —NR²⁸R²⁹ whereR²⁸ and R²⁹ are, independently of each other, hydrogen, alkyl orheteroalkyl; (y) cycloalkylalkyl, cycloalkylalkynyl andcycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxyor amino; (z) arylaminoalkylene or heteroarylaminoalkylene; (aa)Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—, —N(alkyl)— or—O—, and R³⁰, R³¹ and R³² are independently of each other, hydrogen,alkyl or heteroalkyl; (bb) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (whereR′ and R″ are independently hydrogen or alkyl); (cc)heteroarylalkenylene or heteroarylalkynylene; (dd)X-(alkylene)CH[(CR′R″)_(m)OR⁴⁰][(CR′R″)_(n)OR⁴⁰] where: X is —O—, —NH—,—NR— (where R is alkyl), —S(O)_(p)— (where p is an integer from 0 to 2);R⁴⁰ is acyl, C(O)OR⁴¹ (where R⁴¹ is hydrogen, alkyl, or cycloalkyl);C(O)ONR⁴¹R⁴² (where R⁴¹ is as defined above and R⁴² is hydrogen oralkyl); or C(O)NR⁴¹R⁴² (where R⁴¹ and R⁴² are as defined above); R′ andR″, independently, are hydrogen or alkyl; and m and n, independently,are an integer from 0 to 3 provided that m and n are not both zero; (ee)X-(alkylene)-CH(OH)CH₂NHR⁵⁰ where: X is —O—, —NH—, —NR— (where R isalkyl), or —S(O)_(n)— (where n is an integer from 0 to 2); and R⁵⁰ isC(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, or cycloalkyland R⁵² is hydrogen or alkyl); and (ff) X-(alkylene)-CH(NR⁵⁰)—CH₂OHwhere: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2); and R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (whereR⁵¹ is hydrogen, alkyl, or cycloalkyl and R⁵² is hydrogen or alkyl); andR⁴ is selected from the group consisting of: (a) hydrogen; (b) halo; (c)alkyl; (d) alkoxy; and (e) hydroxy; R⁵ is selected from the groupconsisting of: (a) hydrogen; (b) halo; (c) alkyl; (d) haloalkyl; (e)thioalkyl; (f) hydroxy; (g) amino; (h) alkylamino; (i) dialkylamino; (j)heteroalkyl; (k) optionally substituted heterocycle; (l) optionallysubstituted heterocyclylalkyl; (m) optionally substitutedheterocyclylalkoxy; (n) alkylsulfonyl; (o) aminosulfonyl,mono-alkylaminosulfonyl or dialkylaminosulfonyl; (p) heteroalkoxy; and(q) carboxy; R⁶ is selected from a group consisting of: (a) hydrogen;(b) halo; (c) alkyl; and (d) alkoxy; and prodrugs, individual isomers,mixtures of isomers and pharmaceutically acceptable salts thereof. 2.The compound of claim 1 wherein R³ is: (a) optionally substitutedheterocyclyl; (b) aryl or heteroaryl both optionally substituted with asubstituent selected from halo, alkyl, amino, alkoxy, carboxy, loweralkoxy carbonyl, SO₂R′ (where R′ is alkyl) or SO₂NHR′R″ (where R′ and R″are independently hydrogen or alkyl); (c) heteroalkyl; (d)heteroalkenyl; (e) heteroalkylamino; (f) heteroalkoxy; (g) optionallysubstituted heterocyclylalkyl, heterocyclyloxy cycloalkoxy, orcycloalkylalkyloxy; (h) optionally substituted heterocyclylalkenyl; (i)optionally substituted heterocyclylalkynyl; (j) optionally substitutedheterocyclylalkoxy; (k) optionally substituted heterocyclylalkylamino orcycloalkylamino; (l) optionally substituted heterocyclylalkylcarbonyl;(k) —Y-(alkylene)-R⁹ where Y is a single bond, —O— or —N— and R⁹ isoptionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴, —SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ R¹⁷, R¹⁸ andR¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl; (l)cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionallysubstituted with alkyl, halo, hydroxy or amino; (m) arylaminoalkylene orheteroarylaminoalkylene; or (n) Z-alkylene-NR³OR³¹ where Z is —NH—,—N(alkyl)- or —O—, and R³⁰ and R³¹ are independently of each other,hydrogen, alkyl or heteroalkyl.
 3. The compound of claim 2 wherein R¹and R² are hydrogen; and B is phenyl.
 4. The compound of claim 3 whereinA is phenyl.
 5. The compound of claim 4 wherein R⁴ is hydrogen; and R⁵is halo or alkyl.
 6. The compound of claim 5 wherein R⁵ is chloro,fluoro or methyl; and R⁶ is hydrogen, chloro, fluoro, methyl or methoxy.7. The compound of claim 5, wherein R³ is optionally substitutedheteroaryl.
 8. The compound of claim 7, wherein R³ is pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yl, N-oxidopyridin-3-yl,N-oxidopyridin-4-yl or pyridon-2-yl, all optionally substituted.
 9. Thecompound of claim 8, wherein R³ is at the 3-position.
 10. The compoundof claim 9, wherein R⁵ is 4-F and R⁶ is hydrogen.
 11. The compound ofclaim 9, wherein R⁵ is 2-Me and R⁶ is hydrogen.
 12. The compound ofclaim 5, wherein R³ is optionally substituted phenyl.
 13. The compoundof claim 12, wherein R³ is 3-sulfamoylphenyl, 3-methylsulfonylphenyl,3-carboxyphenyl or 3-ethoxycarbonylphenyl.
 14. The compound of claim 13,wherein R³ is at the 3-position.
 15. The compound of claim 14, whereinR⁵ is 4-F and R⁶ is hydrogen.
 16. The compound of claim 5, wherein R³is: (a) heteroalkyl; (b) heteroalkoxy; (c) heteroalkylamino; (d)optionally substituted heterocyclylalkyl; (e) optionally substitutedheterocyclylalkoxy; cycloalkoxy; or cycloalkylalkyloxy; (f) optionallysubstituted heterocyclylalkylamino; (g) —Y-(alkylene)-R⁹ where Y is asingle bond, —O— or —N— and R⁹ is optionally substituted heteroaryl,—CONR¹²R¹³, SO₂R¹⁴, —SO₂NR¹⁵R¹⁶ —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are independently of each otherhydrogen, alkyl or heteroalkyl; or (h) Z-alkylene-NR³⁰R³¹ where Z is—NH—, —N(alkyl)- or —O—, and R³⁰ and R³¹ are independently of eachother, hydrogen, alkyl or heteroalkyl.
 17. The compound of claim 16,wherein R³ is heteroalkyl.
 18. The compound of claim 17, wherein R³ isat the3-position and is selected from the group consisting of2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl,hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or3-hydroxybutyl.
 19. The compound of claim 18, wherein R⁵ is 2-F and R⁶is 4-F.
 20. The compound of claim 18, wherein R⁵ is 4-F and R⁶ ishydrogen.
 21. The compound of claim 18, wherein R⁵ is 2-Me and R⁶ ishydrogen.
 22. The compound of claim 16, wherein R³ is heteroalkoxy orheteroalkylamino.
 23. The compound of claim 22, wherein R³ is at the3-position and is selected from the group consisting of3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy,2,3-dihydroxypropoxy, 2,2-(dihydroxymethyl)ethoxy,2-dimethylaminoethylamino and 3-dimethylaminopropylamino.
 24. Thecompound of claim 23 wherein R⁵ is 4-F or 2-Me and R⁶ is hydrogen. 25.The compound of claim 16, wherein R³ is optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkoxy oroptionally substituted heterocyclylalkylamino.
 26. The compound of claim25, wherein R³ is at the 3-position and is selected from the groupconsisting of 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy,2-(2-oxo-pyrrolidin-1-yl)ethoxy, 3-(morpholin-4-yl)propyl,2-(morpholin-4-yl)ethyl, 4-(morpholin-4-yl)butyl,3-(morpholin-4-yl)propylamino, 2-(morpholin-4-yl)ethylamino,4-hydroxypiperidinylmethyl, 2-(S,S-dioxo-thiamorpholin-4-yl)ethyl,3-(S,S-dioxo-thiamorpholin-4-yl)propyl and N-methylpiperazinylmethyl.27. The compound of claim 26 wherein R⁵ is 4-F or 2-Me and R⁶ ishydrogen.
 28. The compound of claim 25, wherein R³ is at the 3-positionand is selected from the group consisting of(2,2-dimethyl-1,3-dioxolan-4(S)-yl)methoxy,(1,3-dioxolan-2-on-4(R)-yl)methoxy, (2-thioxo-1,3-dioxolan-4-yl)methoxy,(2,2-diethyl-1,3-dioxolan4(S)-yl)methoxy,(2,2-diethyl-1,3-dioxolan-4(S)-yl)methylamino and(2-methyl-2-ethyl-1,3-dioxolan-4(S)-yl)methoxy.
 29. The compound ofclaim 28 wherein R⁵ is 4-F or 2-Me and R⁶ is hydrogen.
 30. The compoundof claim 16 wherein R³ is —Y-(alkylene)-R⁹ where Y is a single bond, —O—or —N— and R⁹ is optionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴,—SO₂NR¹⁵R¹⁶ —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶R¹⁷, R¹⁸ and R¹⁹ are independently of each other hydrogen, alkyl orheteroalkyl.
 31. The compound of claim 30, wherein Y is a single bondand R⁹ is SO₂R¹⁴ or —SO₂NR¹⁵R¹⁶.
 32. The compound of claim 31 wherein R³is methylsulfonylethyl or sulfamoylethyl.
 33. The compound of claim 32wherein R⁵ is 4-F or 2-Me and R⁶ is hydrogen.
 34. The compound of claim1 wherein R³ is selected from the group consisting of: (a) —S(O)_(n)R²⁷where n is an integer from 0 to 2, and R²⁷ is alkyl, heteroalkyl,optionally substituted cycloalkyl, optionally substitutedheterocyclylalkyl, or —NR²⁸R²⁹ where R²⁸ and R²⁹ are, independently ofeach other, hydrogen, alkyl or heteroalkyl; (b)X-(alkylene)CH[(CR′R″)_(m)OR⁴⁰][(CR′R″)_(n)OR⁴⁰] where: X is —O—, —NH—,—NR— (where R is alkyl), —S(O)_(p)— (where p is an integer from 0 to 2);R⁴⁰ is acyl, C(O)OR⁴¹ (where R⁴¹ is hydrogen, alkyl, or cycloalkyl);C(O)ONR⁴¹R⁴² (where R⁴¹ is as defined above and R⁴² is hydrogen oralkyl); or C(O)NR⁴¹R⁴² (where R⁴¹ and R⁴² are as defined above); R′ andR″, independently, are hydrogen or alkyl; and m and n, independently,are an integer from 0 to 3 provided that m and n are not both zero; (c)X-(alkylene)-CH(OH)CH₂NHR⁵⁰ where: X is —O—, —NH—, —NR— (where R isalkyl), or —S(O)_(n)— (where n is an integer from 0 to 2); and R⁵⁰ isC(O)OR⁵¹ and C(O)NR⁵¹R⁵² (where R⁵¹ is hydrogen, alkyl, or cycloalkyland R⁵² is hydrogen or alkyl); and (d) X-(alkylene)-CH(NR⁵⁰)—CH₂OHwhere: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)_(n)— (where nis an integer from 0 to 2); and R⁵⁰ is C(O)OR⁵¹ and C(O)NR⁵¹R⁵² (whereR⁵¹ is hydrogen, alkyl, or cycloalkyl and R⁵² is hydrogen or alkyl) 35.The compound of claim 34, wherein R³ is at the 3-position and is X(alkylene)CH[(CR′R″)_(m)OR⁴⁰][(CR′R″)_(n)OR⁴⁰] where: X is —O—, —NH—,—NR— (where R is alkyl), —S(O)_(p)— (where p is an integer from 0 to 2);R⁴⁰ is acyl, C(O)OR⁴¹ (where R⁴¹ is hydrogen, alkyl, or cycloalkyl);C(O)ONR⁴¹R⁴² (where R⁴¹ is as defined above and R⁴² is hydrogen oralkyl); or C(O)NR⁴¹R⁴² (where R⁴¹ and R⁴² are as defined above); R′ andR″, independently, are hydrogen or alkyl; and m and n, independently,are an integer from 0 to 3 provided that m and n are not both zero. 36.The compound of claim 35, wherein R³ is at the 3-position and isselected from the group consisting of (diacetoxy)propoxy,(diisobutanoyloxy)propoxy, and (dipivaloyloxy)propoxy,(dimethoxycarbonyloxy)propoxy.
 37. The compound of claim 36 wherein R⁴is hydrogen, R⁵ is 4-F or 2-Me and R⁶ is hydrogen.
 38. The compound ofclaim 37 wherein R¹ and R² are hydrogen and A and B are phenyl.
 39. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable excipient.40. A method of treatment of a disease in a mammal treatable byadministration of a p38 MAP kinase inhibitor, comprising administrationto the mammal a therapeutically effective amount of a compound ofclaim
 1. 41. The method of claim 40 wherein the disease is aninflammatory disease.
 42. The method of claim 41 wherein the disease isarthritis.
 43. A process for preparing a compound of Formula (I)selected from compounds of claim 1, which process comprises: (i)reacting a 2-keto-3-phenylaminoacrylonitrile of Formula 1:

with a hydrazine of Formula 2:

where R³, R⁴ R⁵ and R⁶ are as defined in claim 1 to provide a compoundof Formula (I) where R¹ is hydrogen; or (ii) reacting a2-keto-3-phenylaminoacrylonitrile of formula 3:

where Z is either hydroxy, nitro or halo group and R⁴ are as defined inclaim 1 with a hydrazine of formula 2 to provide a compound of formula4:

followed by conversion of the Z group to the desired R³ group to providea compound of Formula (I) where R¹ is hydrogen; (iii) optionallymodifying any of the R¹, R³, R⁴, R⁵ or R⁶ groups; (iv) optionallyconverting the compound of Formula (I) prepared in Steps (i), (ii) or(iii) above, to the corresponding acid addition salt by treatment withan acid; (v) optionally converting the compound of Formula (I) preparedin Steps (i), (ii) or (iii) above, to the corresponding free base bytreatment with a base; and (vi) optionally separating a mixture ofstereoisomers of a compound of Formula (I) prepared in Steps (i)-(v)above, to give a single stereoisomer.
 44. A process for preparing acompound of Formula (I) selected from compounds of claim 1, whichprocess comprises reacting a compound of Formula 5:

where L is a leaving group under organometallic displacement reactionconditions with an organometallic reagent of formula

where M is a metallic moiety to provide a compound of Formula (I) whereR¹ is hydrogen; (ii) optionally modifying any of the R¹, R³, R⁴, R⁵ orR⁶ groups; (iii) optionally converting the compound of Formula (I)prepared in Steps (i) or (ii) above, to the corresponding acid additionsalt by treatment with an acid; (iv) optionally converting the compoundof Formula (I) prepared in Steps (i) or (ii) above, to the correspondingfree base by treatment with a base; and (v) optionally separating amixture of stereoisomers of a compound of Formula (I) prepared in Steps(i) or (iv) above, to give a single stereoisomer.